Human adam-10 inhibitors

ABSTRACT

The present invention provides compounds useful for inhibiting the ADAM-10 protein. Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in combination with a pharmaceutically acceptable carrier. Such compositions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role. The invention also provides methods for making bis-aryl ether sulfonyl chlorides and ADAM-10 modulators therefrom.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 10/498,338, nowallowed, which is a U.S. national phase of international applicationPCT/US02/39816 filed on Dec. 13, 2002, which claims priority to U.S.Provisional Patent Application Ser. No. 60/340,179 filed on Dec. 14,2001, the disclosures of which are incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention is in the field of agents that inhibit humanADAM-10 (also known as human Kuzbanian) and their use in the treatmentof cancer, arthritis, and diseases related to angiogenesis, such asrenal diseases, heart diseases such as heart failure, atherosclerosis,and stroke, inflammation, ulcer, infertility, scleroderma,endometriosis, mesothelioma, and diabetes.

SUMMARY OF THE RELATED ART

Cell-cell interactions play an important role in regulating cell fatedecisions and pattern formation during the development of multicellularorganisms. One of the evolutionarily conserved pathways that plays acentral role in local cell interactions is mediated by the transmembranereceptors encoded by the Notch (N) gene of Drosophila, the lin-12 andglp-1 genes of C. elegans, and their vertebrate homologs (reviewed inArtavanis-Tsakonas, S., et al. (1995) Notch Signaling. Science 268,225-232), collectively hereinafter referred to as NOTCH receptors.Several lines of evidence suggest that the proteolytic processing ofNOTCH receptors is important for their function. For example, inaddition to the full length proteins, antibodies against theintracellular domains of NOTCH receptors have detected C-terminalfragments of 100-120 kd; see, e.g., Fehon, R. G., et al. (1990). Cell61, 523-534; Crittenden, S. L., et al. (1994). Development 120,2901-2911; Aster, J., et al. (1994) Cold Spring Harbor Symp. Quant.Biol. 59, 125-136; Zagouras, P., et al. (1995). Proc. Natl. Acad. Sci.U.S.A. 92, 6414-6418; and Kopan, R., et al. (1996). Proc. Natl. Acad.Sci. U.S.A. 93, 1683-1688. However, the mechanism(s) of NOTCH activationhave been hitherto largely unknown.

During neurogenesis, a single neural precursor is singled out from agroup of equivalent cells through a lateral inhibition process in whichthe emerging neural precursor cell prevents its neighbors from taking onthe same fate (reviewed in Simpson, P. (1990). Development 109,509-519). Genetic studies in Drosophila have implicated a group of“neurogenic genes” including N in lateral inhibition. Loss-of-functionmutations in any of the neurogenic genes result in hypertrophy of neuralcells at the expense of epidermis (reviewed in Campos-Ortega, J. A.(1993) In: The Development of Drosophila melanogaster M. Bate and A.Martinez-Arias, eds. pp. 1091-1129. Cold Spring Harbor Press.).

Rooke, J., Pan, D. J., Xu, T. and Rubin, G. M. (1996). Science 273,1227-1231, discloses neurogenic gene family, kuzbanian (kuz). Members ofthe KUZ family of proteins are shown to belong to the recently definedADAM family of transmembrane proteins, members of which contain both adisintegrin and metalloprotease domain (reviewed in Wolfsberg, T. G. etal., (1995). J. Cell Biol. 131, 275-278, see also Blobel, C. P., et al.(1992). Nature 356, 248-252, 1992; Yagami-Hiromasa, T., et al. (1995).Nature 377, 652-656; Black, R. A., et al. (1997). Nature 385, 729-733,1997; and Moss, M. L., et al. (1997). Nature 385, 733-736; see also U.S.Pat. No. 5,922,546 and U.S. Pat. No. 5,935,792).

Genes of the ADAM family encode transmembrane proteins containing bothmetalloprotease and disintegrin domains (reviewed in Black and White,1998 Curr. Opin. Cell Biol. 10, 654-659; Wolfsberg and White, 1996 Dev.Biol. 180, 389-401), and are involved in diverse biological processes inmammals such as fertilization (Cho et al., 1998 Science 281, 1857-1859),myoblast fusion (Yagami-Hiromasa et al., 1995 Nature 377, 652-656) andectodomain shedding (Moss et al., 1997 Nature 385, 733-736; Black etal., 1997 Nature 385, 729-733; Peschon et al., 1998 Science 282,1281-1284). The Drosophila kuzbanian (kuz) gene represents the firstADAM family member identified in invertebrates (Rooke et al., 1996Science 273, 1227-1231). Previous genetic studies showed that kuz isrequired for lateral inhibition and axonal outgrowth during Drosophilaneural development (Rooke et al., 1996; Fambrough et al., 1996 PNAS. USA93, 13233-13238; Pan and Rubin, 1997 Cell 90, 271-280; Sotillos et al.,1997 Development 124, 4769-4779). Specifically, during the lateralinhibition process, kuz acts upstream of Notch (Pan and Rubin, 1997;Sotillos et al., 1997), which encodes the transmembrane receptor for thelateral inhibition signal encoded by the Delta gene. More recently, ahomolog of kuz was identified in C. elegans (SUP-17) that modulates theactivity of a C. elegans homolog of Notch in a similar manner (Wen etal., 1997 Development 124, 4759-4767).

Vertebrate homologs of kuz have been isolated in Xenopus, bovine, mouse,rat and human. The bovine homolog of KUZ (also called MADM or ADAM 10)was initially isolated serendipitously based on its in vitro proteolyticactivity on myelin basic protein, a cytoplasmic protein that is unlikelythe physiological substrate for the bovine KUZ protease (Howard et al.,1996 Biochem. J. 317, 45-50). Expression of a dominant negative form ofthe murine kuz homolog (mkuz) in Xenopus leads to the generation ofextra neurons, suggesting an evolutionarily conserved role for mkuz inregulating Notch signaling in vertebrate neurogenesis (Pan and Rubin,1997). U.S. patent application. No. 09/697,854, to Pan et al., filedOct. 27, 2000, discloses that mkuz mutant mice die around embryonic day(E) 9.5, with severe defects in the nervous system, the paraxialmesoderm and the yolk sac vasculature. In the nervous system, mkuzmutant embryos show ectopic neuronal differentiation. In the paraxialmesoderm, mkuz mutant embryos show delayed and uncoordinatedsegmentation of the somites. These phenotypes are similar to those ofmice lacking Notch-1 or components of the Notch pathway such as RBP-Jk(Conlon et al, 1995, Development 121, 1533-1545; Oka et al., 1995),indicating a conserved role for mkuz in modulating Notch signaling inmouse development. Furthermore, no visible defect was detected in Notchprocessing in the kuz knockout animals. In addition to the neurogenesisand somitogenesis defect, mkuz mutant mice also show severe defects inthe yolk sac vasculature, with an enlarged and disordered capillaryplexus and the absence of large vitelline vessels. Since such phenotypehas not been observed in mice lacking Notch-1 or RBP-Jk (Swiatek et al.,1994 Genes Dev 15, 707-719; Conlon et al., 1995; Oka et al., 1995Development 121, 3291-3301), Pan et al. determined that this phenotypereveals a novel function of mkuz that is distinct from its role inmodulating Notch signaling, specifically, that kuz plays an essentialrole for an ADAM family disintegrin metalloprotease in mammalianangiogenesis.

In view of the important role of KUZ (ADAM-10) in biological processesand disease states, inhibitors of this protein are desirable.

All patents, applications, and publications recited herein are herebyincorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention provides compounds useful for inhibiting orotherwise modulating the activity of the ADAM-10 protein. Such compoundsare useful in the in vitro study of the role of ADAM-10 (and itsinhibition) in biological processes. The present invention alsocomprises pharmaceutical compositions comprising one or more ADAM-10inhibitors according to the invention in combination with apharmaceutically acceptable carrier. Such compositions are useful forthe treatment of cancer, arthritis, and diseases related toangiogenesis. Correspondingly, the invention also comprises methods oftreating forms of cancer, arthritis, and diseases related toangiogenesis in which ADAM-10 plays a critical role.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises inhibitors of ADAM-10. In oneembodiment, the invention comprises a compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R₁ is selected from hydrogen, alkyl, alkanoyl, arylalkyl, and        arylalkanoyl, wherein        -   the arylalkyl and arylalkanoyl groups are unsubstituted or            substituted with 1, 2, 3, 4, or 5 R₆ groups;    -   R₆ at each occurrence is independently selected from halogen,        hydroxy, —NO₂, —CO₂R₁₀, —CN, alkyl, alkoxy, haloalkyl, and        haloalkoxy;    -   R₂ is selected from hydrogen, alkyl, alkoxy, alkanoyl, arylalkyl        and arylalkanoyl, wherein        -   the arylalkyl and arylalkanoyl groups are unsubstituted or            substituted with 1, 2, 3, 4, or 5 R₆ groups;    -   R₃ is -Z-Q-J, wherein        -   Z is selected from alkyl, alkoxyalkyl, alkylthioalkyl, and            alkenyl, each of which is unsubstituted or substituted with            1 or 2 groups that are independently selected from alkoxy,            hydroxy, and halogen;        -   Q is selected from a direct bond between Z and J, —C(═O)—,            aryl, heteroaryl, and heterocycloalkyl, wherein            -   the aryl, heteroaryl, or heterocycloalkyl group is                unsubstituted or substituted with 1 or 2 groups that are                independently selected from alkyl, halogen, —NR₆R₉ and                alkoxy;        -   J is selected from —NR₈R₉, —NR₇C(═O)NR₈R₉, —NR₇C(═O)            alkylNR₈R₉, —NR₇C(═O)OR₉, —C(═NR₇)NR₈R₉, and            —NH—C(═NR₇)NR₈R, wherein        -   R₇ is selected from H, CN, NO₂, alkyl, alkanoyl,            arylalkanoyl and —C(═O)NR₁₀R₁₁, wherein            -   R₁₀ and R₁₁, are independently selected from H, and                alkyl, and        -   R₈ and R₉ are independently selected from H, alkyl, hydroxy,            alkoxy, alkoxyalkyl, heterocycloalkylalkyl, arylalkyl, and            heteroarylalkyl, wherein each of the above is unsubstituted            or substituted with 1, 2, 3, or 4 R₆ groups; or        -   R₈ and R₉ and the nitrogen to which they are attached form a            5, 6 or 7 membered heterocycloalkyl ring, which is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently selected from alkyl, alkoxy, hydroxy, and            halogen; or        -   R₇, R₈, and the nitrogens to which they are attached form a            5, 6 or 7 membered heterocycloalkyl group that is            unsubstituted or substituted with 1, 2 or 3 groups that are            independently selected from alkyl, alkoxy, hydroxy, and            halogen; and        -   R₉ is selected from H, alkyl, hydroxy, alkoxy, alkoxyalkyl,            heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl,            wherein each of the above is unsubstituted or substituted            with 1, 2, 3, or 4 R₆ groups;    -   R₄ is selected from H, alkyl, and arylalkyl, wherein the        arylalkyl group is unsubstituted or substituted with 1, 2, 3, 4,        or 5 R₆ groups; and    -   R₅ is -M-G-A, wherein    -   M is selected from aryl and heteroaryl, wherein M is        unsubstituted or substituted with 1, 2, 3, or 4 groups that are        independently selected from halogen, alkyl, hydroxy, alkoxy,        haloalkyl, —CN, haloalkoxy, and hydroxyalkyl;    -   G is selected from a direct bond between M and A, CH₂,        -alkyl-O—, —O-alkyl-, O, S, SO, and SO₂;    -   A is selected from aryl and heteroaryl, wherein A is        unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that        are independently selected from halogen, alkyl, alkoxy,        haloalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy,        haloalkoxy, —CN, and NO₂;    -   with the proviso that when M is phenyl, G is a direct bond        between M and A, and A is phenyl, then at least one of the four        remaining hydrogens on the phenyl ring of M, of M-G-A, must be        substituted with a group independently selected from halogen,        alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and        hydroxyalkyl;

In one example, the invention comprises a compound of formula I asdescribed in paragraph [0010], wherein

-   -   R₁ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, phenyl C₁-C₆ alkyl, and phenyl C₁-C₆ alkanoyl, wherein        the phenylalkyl and phenylalkanoyl groups are unsubstituted or        substituted with 1, 2, 3, 4, or 5 R₆ groups, and    -   R₂ is selected from the group consisting of hydrogen, C₁-C₆        alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl and phenyl C₁-C₆        alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups are        unsubstituted or substituted with 1, 2, 3, 4, or 5 R₆ groups,    -   wherein R₆ at each occurrence is independently selected from the        group consisting of halogen, hydroxy, —NO₂, —CN, C₁-C₆ alkyl,        C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound of formula I asdescribed in paragraph [0010], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 groups independently selected from            C₁-C₄ alkyl, halogen, and C₁-C₄ alkoxy;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl,            thiomorpholinyl, azepanyl, or azocanyl wherein            -   each is unsubstituted or substituted with 1 or 2 groups                that are independently selected from C₁-C₄ alkyl,                halogen, and C₁-C₄ alkoxy;        -   J is —C(═NR₇)NR₈R₉, or —NH—C(═NR₇)NR₈R₉, wherein        -   R₇ is selected from the group consisting of H, —CN, —NO₂,            C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl and            —C(═O)NR₁₀R₁₁, wherein            -   R₁₀ and R₁₁ are independently selected from H and C₁-C₆                alkyl,        -   R₈ and R₉ are each independently selected from the group            consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy            C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl,            thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide,            piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl,            imidazolidinyl C₁-C₆ alkyl, C₁-C₈ cycloalkyl, C₃-C₈            cycloalkyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, and pyridyl            C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl,            pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, and furyl C₁-C₆            alkyl, wherein each of the above is unsubstituted or            substituted with 1, 2, 3, or 4 R₆ groups; or    -   R₈ and R₉ and the nitrogen to which they are attached form a 5,        6 or 7 membered heterocycloalkyl ring, which is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, and halogen;    -   or        -   R₇, R₈, and the nitrogens to which they are attached form a            5, 6 or 7 membered heterocycloalkyl group that is            unsubstituted or substituted with 1, 2 or 3 groups that are            independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy,            hydroxy, and halogen; and        -   R₉ is selected from the group consisting of H, C₁-C₆ alkyl,            C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈ cycloalkyl,            and C₁-C₆ alkyl substituted with at least one of            morpholinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl            S-oxide, phenyl, naphthyl, thiomorpholinyl S,S-dioxide,            pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and            imidazolyl,        -   wherein each of the above is unsubstituted or substituted            with 1, 2, 3, or 4 R₆ groups, wherein        -   R₆ at each occurrence is independently selected from the            group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,            C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound of formula I asdescribed in paragraph [0010], wherein

-   -   R₅ is -M-G-A, wherein    -   M is selected from the group consisting of phenyl, pyridyl,        pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl,        wherein M is unsubstituted or substituted with 1, 2, 3, or 4        groups that are independently selected from the group consisting        of halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halo C₁-C₆        alkyl, halo C₁-C₆ alkoxy, and hydroxy C₁-C₆ alkyl,    -   G is selected from a direct bond between M and A, CH₂, O, S, SO,        and SO₂;    -   A is selected from the group consisting of phenyl, naphthyl,        pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl,        benzo[1,3]dioxyl, quinolinyl, isoquinolinyl,        tetrahydroisoquinolinyl, tetrahydronaphthyl, and        dihydronaphthyl, wherein each of the above is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆        alkyl, halo C₁-C₆ alkoxy, CN, and NO₂;    -   with the proviso that when M is phenyl, G is a direct bond        between M and A, and A is phenyl, then at least one of the four        remaining hydrogens on the phenyl ring of M, of M-G-A, must be        substituted with a group independently selected from halogen,        alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and        hydroxyalkyl.

In another example, the invention comprises a compound of formula I asdescribed in paragraph [0010], wherein

-   -   R₁ is hydrogen, C₁-C₆ alkyl or benzyl;    -   R₂ is hydrogen, C₁-C₆ alkyl or benzyl; and    -   R₃ is -Z-Q-J, wherein        -   Z is C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl,            thiomorpholinyl, azepanyl, or azocanyl wherein each of the            above is unsubstituted or substituted with 1 or 2 groups            that are independently C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy;        -   J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein        -   R₇ is selected from the group consisting of H, —CN, —NO₂,            C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl and            —C(═O)NR₁₀R₁₁, wherein            -   R₁₀, and R₁₁ are independently H, or C₁-C₆ alkyl, and        -   R₈ and R₉ are independently selected from the group            consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy            C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl,            thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide,            piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl,            imidazolidinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈            cycloalkyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, and pyridyl            C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl,            pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, and furyl C₁-C₆            alkyl, wherein each of the above is unsubstituted or            substituted with 1, 2, 3, or 4 R₆ groups; or

R₈ and R₉ and the nitrogen to which they are attached form a 5, 6 or 7membered heterocycloalkyl ring, which is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently selected from C₁-C₆ alkyl,C₁-C₆alkoxy, hydroxy, and halogen;

-   -   or        -   R₇, R₈, and the nitrogens to which they are attached form a            5, 6, or 7 membered heterocycloalkyl group that is            unsubstituted or substituted with 1, 2 or 3 groups that are            independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,            hydroxy, and halogen, wherein each of the above is            unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups,            wherein R₆ at each occurrence is independently selected from            the group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,            C₁-C₆ alkoxy, CF₃, and OCF₃; and        -   R₉ is selected from the group consisting of H, C₁-C₆ alkyl,            C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈ cycloalkyl,            and C₁-C₆ alkyl substituted with at least one of            morpholinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl            S-oxide, phenyl, naphthyl, thiomorpholinyl S,S-dioxide,            pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and            imidazolyl, wherein each of the above is unsubstituted or            substituted with 1, 2, 3, or 4 R₆ groups;    -   R₄ is selected from the group consisting of H, C₁-C₄ alkyl,        benzyl and phenethyl, wherein the benzyl and phenethyl groups        are unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups;    -   R₅ is -M-G-A, wherein        -   M is selected from the group consisting of phenyl, pyridyl,            pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl,            wherein M is unsubstituted or substituted with 1, 2, 3, or 4            groups that are independently selected from the group            consisting of halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,            halo C₁-C₆ alkyl, halo C₁-C₆ alkoxy, and hydroxy C₁-C₆            alkyl,        -   G is selected from a direct bond between M and A, CH₂, O, S,            SO, and SO₂;        -   A is selected from the group consisting of phenyl, naphthyl,            pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl,            benzo[1,3]dioxyl, quinolinyl, isoquinolinyl,            tetrahydroisoquinolinyl, tetrahydronaphthyl, and            dihydronaphthyl, wherein each of the above is unsubstituted            or substituted with 1, 2, 3, 4, or 5 groups that are            independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆            alkyl, halo C₁-C₆ alkoxy, CN, or NO₂;        -   with the proviso that when M is phenyl, G is a direct bond            between M and A, and A is phenyl, then at least one of the            four remaining hydrogens on the phenyl ring of M, of M-G-A,            must be substituted with a group independently selected from            halogen, alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy,            and hydroxyalkyl.

In another example, the invention comprises a compound as in paragraph[0014], wherein

-   -   R₅ is -M-G-A, wherein    -   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,        thiophenyl, and pyrrolyl, each of which is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        selected from the group consisting of F, Cl, Br, C₁-C₄ alkyl,        hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄        alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl;        -   G is selected from a direct bond between M and A, CH₂, O, S,            SO, and SO₂;    -   A is selected from the group consisting of phenyl, naphthyl,        pyridyl, pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl,        isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, and        dihydronaphthyl, wherein each is unsubstituted or substituted        with 1, 2, or 3 groups that are independently selected from the        group consisting of F, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo        C₁-C₄ alkyl, CF₃, OCF₃, —CN, and —NO₂;    -   with the proviso that when M is phenyl, G is a direct bond        between M and A, and A is phenyl, then at least one of the four        remaining hydrogens on the phenyl ring of M, of M-G-A, must be        substituted with a group independently selected from halogen,        alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and        hydroxyalkyl.

In another example, the invention comprises a compound as in paragraph[0015], wherein

-   -   R₃ is -Z-Q-J, wherein    -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆ alkylthio        C₁-C₆ alkyl, each of which is unsubstituted or substituted with        1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups;    -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,        pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or        thiomorpholinyl, wherein each is unsubstituted or substituted        with 1 or 2 groups that are independently C₁-C₄alkyl, halogen,        or C₁-C₄ alkoxy;    -   J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein        -   R₁ is selected from the group consisting of H, CN, NO₂,            C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein            -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl, and        -   R₈ and R₉ are independently selected from the group            consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy            C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl, C₃-C₈            cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein each            of the above is unsubstituted or substituted with 1, 2, 3,            or 4 R₆ groups; wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃,        -   or        -   R₈ and R₉ and the nitrogen to which they are attached form a            5 or 6 membered heterocycloalkyl ring, which is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently C₁-C₆ alkyl, C₁-C₆alkoxy, hydroxy, or halogen.

In another example, the invention comprises a compound as in paragraph[0016], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl,            morpholinyl, or thiomorpholinyl, wherein each is            unsubstituted or substituted with 1 or 2 groups that are            independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; and        -   J is —C(═NR₇)NR₈R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl, and            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,                thiomorpholinyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl                C₁-C₆ alkyl, wherein each of the above is unsubstituted                or substituted with 1, 2, 3, or 4 R₆ groups, wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃,            -   or            -   R₈, and R₉ and the nitrogen to which they are attached                form a 5 or 6 membered heterocycloalkyl ring, which is                unsubstituted or substituted with 1, 2, or 3 groups that                are independently C₁-C₆ alkyl, C₁-C₆alkoxy, hydroxy, or                halogen.

In another example, the invention comprises a compound as in paragraph[0016], wherein

-   -   R₈, and R₉ and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or        pyrrolidinyl ring, each of which is unsubstituted or substituted        with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆        alkoxy, hydroxy, or halogen.

In another example, the invention comprises a compound as in paragraph[0015], wherein

-   -   R₃ is -Z-Q-J wherein    -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆ alkylthio        C₁-C₆ alkyl, each of which is unsubstituted or substituted with        1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups;    -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,        pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or        thiomorpholinyl, wherein each is unsubstituted or substituted        with 1 or 2 groups that are independently C₁-C₄ alkyl, halogen,        or C₁-C₄ alkoxy;    -   J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈NR₉, wherein        -   R₇, R₈, and the nitrogens to which they are attached form a            5, 6, or 7 membered heterocycloalkyl group that is            unsubstituted or substituted with 1, or 2 groups that are            independently C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, or            halogen; and        -   R₉ is selected from the group consisting of H, C₁-C₆ alkyl,            C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈ cycloalkyl,            and C₁-C₆ alkyl substituted with at least one of            morpholinyl, piperidinyl, thiomorpholinyl, phenyl, naphthyl,            pyrrolidinyl, pyridyl, pyridazyl, and imidazolyl, wherein            each of the above is unsubstituted or substituted with 1, or            2 R₆ groups; wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0015], wherein

-   -   R₃ is -Z-Q-J wherein    -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆ alkylthio        C₁-C₆ alkyl, each of which is unsubstituted or substituted with        1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups;    -   Q is piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl,        morpholinyl, or thiomorpholinyl, wherein each is unsubstituted        or substituted with 1 or 2 groups that are independently C₁-C₄        alkyl, halogen, or C₁-C₄ alkoxy; and    -   J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein        -   R₇ is selected from the group consisting of H, CN, NO₂,            C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein            -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl, and        -   R₈ and R₉ are independently selected from the group            consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy            C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl, C₃-C₈            cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein each            of the above is unsubstituted or substituted with 1, 2, 3,            or 4 R₆ groups; wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0010] of structural formula II

wherein R₃, R₄, and R₅ are as defined in paragraph [0010].

In another example, the invention comprises a compound as in paragraph[0021], wherein

-   -   R₄ is selected from the group consisting of H, C₁-C₄ alkyl, and        benzyl wherein the benzyl group is unsubstituted or substituted        with 1, 2, 3, or 4 R₆ groups, wherein    -   R₆ at each occurrence is independently selected from the group        consisting of halogen, hydroxy, —NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy,        CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0022], wherein

-   -   R₅ is -M-G-A, wherein        -   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,            thiophenyl, and pyrrolyl, each of which is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo            C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl;        -   G is selected from a direct bond between M and A, CH₂, O, S,            SO, and SO₂;        -   A is selected from the group consisting of phenyl, naphthyl,            pyridyl, pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl,            isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl,            and dihydronaphthyl, wherein each is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN, and            NO₂;        -   with the proviso that when M is phenyl, G is a direct bond            between M and A, and A is phenyl, then at least one of the            four remaining hydrogens on the phenyl ring of M, of M-G-A,            must be substituted with a group independently selected from            halogen, alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy,            and hydroxyalkyl.

In another example, the invention comprises a compound as in paragraph[0022], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl,            thiomorpholinyl, azepanyl, or azocanyl wherein each is            unsubstituted or substituted with 1 or 2 groups that are            independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy;        -   J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein    -   R₇ is selected from the group consisting of H, CN, NO₂, C₁-C₆        alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl and —C(═O)NR₁₀R₁₁,        wherein        -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,    -   R₈ and R₉₃ are independently selected from the group consisting        of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy C₁-C₆ alkyl,        morpholinyl C₁-C₆ alkyl, thiomorpholinyl, thiomorpholinyl        S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C₁-C₆ alkyl,        pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl, C₃-C₈        cycloalkyl, C₃-C₈ cycloalkyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl,        and pyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, pyrimidyl C₁-C₆        alkyl, pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, and furyl        C₁-C₆ alkyl, wherein each of the above is unsubstituted or        substituted with 1, 2, 3, or 4 R₆ groups; or    -   R₈ and R₉ and the nitrogen to which they are attached form a 5,        6 or 7 membered heterocycloalkyl ring, which is unsubstituted or        substituted with 1, 2, or 3 groups that are independently C₁-C₆        alkyl, C₁-C₆alkoxy, hydroxy, or halogen; or    -   R₇, R₈, and the nitrogens to which they are attached form a 5,        6, or 7 membered heterocycloalkyl group that is unsubstituted or        substituted with 1, 2 or 3 groups that are independently C₁-C₆        alkyl, C₁-C₆ alkoxy, hydroxy, or halogen, wherein each of the        above is unsubstituted or substituted with 1, 2, 3, or 4 R₆        groups; wherein    -   R₆ at each occurrence is independently selected from the group        consisting of halogen, hydroxy, NO, C₁-C₆ alkyl, C₁-C₆ alkoxy,        CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0021] of structural formula III

wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl,            thiomorpholinyl, azepanyl, or azocanyl wherein each is            unsubstituted or substituted with 1 or 2 groups that are            independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy;        -   J is —C(═NR₇)NR₉ or —NH—C(═NR₇)NR₈R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl and                —C(═O)NR₁₀R₁₁, wherein                -   R₁₀, and R₁₁ are independently H, or C₁-C₆ alkyl,            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,                thiomorpholinyl, thiomorpholinyl S,S-dioxide,                thiomorpholinyl S-oxide, piperidinyl C₁-C₆ alkyl,                pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl,                C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl C₁-C₆ alkyl, phenyl                C₁-C₆ alkyl, and pyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆                alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl,                thienyl C₁-C₆ alkyl, and furyl C₁-C₆ alkyl, wherein each                of the above is unsubstituted or substituted with 1, 2,                3, or 4 R₆ groups; or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; or            -   R₇, R₈, and the nitrogens to which they are attached                form a 5, 6, or 7 membered heterocycloalkyl group that                is unsubstituted or substituted with 1, 2 or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; wherein each of the above is                unsubstituted or substituted with 1, 2, 3, or 4 R₆                groups; wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃;    -   and    -   R₅ is -M-G-A, wherein        -   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,            thiophenyl, and pyrrolyl, each of which is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo            C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl;        -   G is selected from a direct bond between M and A, CH₂, O, S,            SO, and SO₂; and        -   A is selected from the group consisting of phenyl, naphthyl,            pyridyl, pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl,            isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl,            and dihydronaphthyl, wherein each is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN, and            NO₂;        -   with the proviso that when M is phenyl, G is a direct bond            between M and A, and A is phenyl, then at least one of the            four remaining hydrogens on the phenyl ring of M, of M-G-A,            must be substituted with a group independently selected from            halogen, alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy,            and hydroxyalkyl.

In another example, the invention comprises a compound as in paragraph[0025], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or            thiomorpholinyl, wherein            -   each is unsubstituted or substituted with 1 or 2 groups                that are independently C₁-C₄ alkyl, halogen, or C₁-C₄                alkoxy;        -   J is —C(═NR₇)NR₈R₉ or —NH—C(═N₇)NR₈R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,            -   R₈ and R₉, are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperidinyl                C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl,                C₃-C₈ cycloalkyl C₁-C₆ alkyl, benzyl, phenethyl, and                pyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, and furyl                C₁-C₆ alkyl, wherein each of the above is unsubstituted                or substituted with 1, 2, 3, or 4 R₆ groups; or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆alkoxy,                hydroxy, or halogen; or            -   R₇, R₈, and the nitrogens to which they are attached                form a 5, 6, or 7 membered heterocycloalkyl group that                is unsubstituted or substituted with 1, 2 or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen;        -   wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃; and    -   R₅ is -M-G-A, wherein        -   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,            thiophenyl, and pyrrolyl, each of which is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo            C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl;        -   G is selected from a direct bond between M and A, CH₂, and            O; and        -   A is selected from the group consisting of phenyl, naphthyl,            pyridyl, tetrahydronaphthyl, benzo[1,3]dioxyl, and            dihydronaphthyl, wherein each is unsubstituted or            substituted with 1, 2, or 3 groups that are independently            selected from the group consisting of F, Cl, Br, C₁-C₄            alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN, and            No₂;        -   with the proviso that when M is phenyl, G is a direct bond            between M and A, and A is phenyl, then at least one of the            four remaining hydrogens on the phenyl ring of M, of M-G-A,            must be substituted with a group independently selected from            halogen, alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy,            and hydroxyalkyl.

In another example, the invention comprises a compound as in paragraph[0026] of structural formula IV

wherein

-   -   R₃ is defined in paragraph [0026], and    -   X is CH, CR₁₂, or N;    -   R₁₂ and R₁₃ are at each occurrence are independently selected        from the group consisting of H, halogen, CF₃, C₁-C₄ alkyl, and        C₁-C₄ alkoxy;    -   A is selected from the group consisting of phenyl, naphthyl,        pyridyl, benzo[1,3]dioxyl, and tetrahydronaphthyl, wherein each        is unsubstituted or substituted with 1, 2, or 3 groups that are        independently selected from the group consisting of F, Cl, Br,        C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN, and        NO₂; and    -   G is selected from a direct bond between M and A, CH₂, and O;    -   with the proviso that when M is phenyl (in this case when X is        equivalent to CH), G is a direct bond between M and A, and A is        phenyl, then at least one of R₁₂ and R₁₃ cannot be H.

In another example, the invention comprises a compound as in paragraph[0027] of structural formula V

wherein

-   -   R₃, is as defined in paragraph [0026],    -   A is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl,        4-cyanophenyl, benzo[1,3]dioxyl, 3,5-dimethylphenyl, 2-naphthyl,        or 2-tetrahydronaphthyl;    -   G is a direct bond between M and A, or G is oxygen; and    -   R₁₂ and R₁₃ are independently H, fluoro, chloro, CF₃, methyl or        methoxy;    -   with the proviso that when G is a direct bond to A, and A is        phenyl, then at least one of R₁₂ and R₁₃ cannot be H.

In another example, the invention comprises a compound as in paragraph[0028], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J or —C(═O)—,    -   J is —NH—C(═NR₇)NR₈R₉, wherein        -   R₇ is selected from the group consisting of H, CN, NO₂,            C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀, R₁₁, wherein            -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl, and        -   R₈ and R₉ are independently selected from the group            consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy            C₁-C₄ alkyl, morpholinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl, and            C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein each of the above is            unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups,            wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃,        -   or        -   R₈ and R₉, and the nitrogen to which they are attached form            a 5, 6 or 7 membered heterocycloalkyl ring, which is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently C₁-C₆ alkyl, C₁-C₆alkoxy, hydroxy, or halogen.

In another example, the invention comprises a compound as in paragraph[0028], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J or —C(O)—,        -   J is —NH—C(═NR₇)NR₈R₉, wherein            -   R₇, R₈, and the nitrogens to which they are attached                form a 5, 6, or 7 membered heterocycloalkyl group that                is unsubstituted or substituted with 1, 2 or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; and            -   R₉ is selected from the group consisting of H, C₁-C₆                alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈                cycloalkyl, and C₁-C₆ alkyl substituted with at least                one of morpholinyl, piperidinyl, thiomorpholinyl,                phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl,                pyrimidyl, pyrazinyl, and imidazolyl, wherein each of                the above is unsubstituted or substituted with 1, 2, 3,                or 4 R₆ groups, wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0028], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, piperidinyl, pyrrolyl,            piperazinyl, imidazolidinyl, morpholinyl, or            thiomorpholinyl, wherein            -   each is unsubstituted or substituted with 1 or 2 groups                that are independently C₁-C₄ alkyl, halogen, or C₁-C₄                alkoxy;        -   J is —C(═NR₇)NR₈R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, C₃-C₈                cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein                each of the above is unsubstituted or substituted with                1, 2, 3, or 4 R₆ groups;            -   or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆alkoxy,                hydroxy, or halogen; wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0027] of structural formula VI

wherein

-   -   R₃, is as defined in paragraph [0027],    -   A is phenyl, 3-fluorophenyl, 4-fluorophenyl, benzo[1,3]dioxyl,        4-chlorophenyl, 4-cyanophenyl, 3,5-dimethylphenyl, 2-naphthyl,        or 2-tetrahydronaphthyl    -   G is a direct bond between M and A, or G is oxygen;    -   R₁₂ is selected from the group consisting of H, halogen, C₁-C₄        alkyl, —CF₃, and C₁-C₄ alkoxy.

In another example, the invention comprises a compound as in paragraph[0032], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J or —C(O)—,        -   J is —NH—C(═NR₇)NR₈R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl, and            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, C₃-C₈                cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein                each of the above is unsubstituted or substituted with                1, 2, 3, or 4 R₆ groups; wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃, or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆alkoxy,                hydroxy, or halogen.

In another example, the invention comprises a compound as in paragraph[0032], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J or —C(═O)—,        -   J is —NH—C(═NR₇)NR₈R₉, wherein            -   R₇, R₈, and the nitrogens to which they are attached                form a 5, 6, or 7 membered heterocycloalkyl group that                is unsubstituted or substituted with 1, 2 or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; and            -   R₉ is selected from the group consisting of H, C₁-C₆                alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈                cycloalkyl, and C₁-C₆ alkyl substituted with at least                one of morpholinyl, piperidinyl, thiomorpholinyl,                phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl,                pyrimidyl, pyrazinyl, and imidazolyl, wherein each of                the above is unsubstituted or substituted with 1, 2, 3,                or 4 R₆ groups, wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound as in paragraph[0032], wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, piperidinyl, pyrrolyl,            piperazinyl, imidazolidinyl, morpholinyl, or            thiomorpholinyl, wherein            -   each is unsubstituted or substituted with 1 or 2 groups                that are independently C₁-C₄ alkyl, halogen, or C₁-C₄                alkoxy;        -   J is —C(═NR₇)NR₈R₉ wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, C₃-C₆                cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein                each of the above is unsubstituted or substituted with                1, 2, 3, or 4 R₆ groups;            -   or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆alkoxy,                hydroxy, or halogen; wherein                -   R₆ at each occurrence is independently selected from                    the group consisting of halogen, hydroxy, NO₂, C₁-C₆                    alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.

In another example, the invention comprises a compound of structuralformula VII:

wherein

-   -   R₃ is -Z-Q-J, wherein        -   Z is a C₁-C₁₀ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆            alkylthio C₁-C₆ alkyl, each of which is unsubstituted or            substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄            alkoxy groups;        -   Q is a direct bond between Z and J, —C(═O)—, piperidinyl,            pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl,            thiomorpholinyl, azepanyl, or azocanyl wherein        -   each is unsubstituted or substituted with 1 or 2 groups that            are independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy;        -   J is —NH—C(═NR₇) NR₃R₉, wherein            -   R₇ is selected from the group consisting of H, CN, NO₂,                C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl and                —C(═O)NR₁₀R₁₁, wherein                -   R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,            -   R₈ and R₉ are independently selected from the group                consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,                alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,                thiomorpholinyl, thiomorpholinyl S,S-dioxide,                thiomorpholinyl S-oxide, piperidinyl C₁-C₆ alkyl,                pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl,                C₃-C₈ cycloalkyl, C₁-C₈ cycloalkyl C₁-C₆ alkyl, phenyl                C₁-C₆ alkyl, and pyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆                alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl,                thienyl C₁-C₆ alkyl, and furyl C₁-C₆ alkyl, wherein each                of the above is unsubstituted or substituted with 1, 2,                3, or 4 R₆ groups; or            -   R₈ and R₉ and the nitrogen to which they are attached                form a 5, 6 or 7 membered heterocycloalkyl ring, which                is unsubstituted or substituted with 1, 2, or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; or            -   R₇, R₈, and the nitrogens to which they are attached                form a 5, 6, or 7 membered heterocycloalkyl group that                is unsubstituted or substituted with 1, 2 or 3 groups                that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                hydroxy, or halogen; wherein each of the above is                unsubstituted or substituted with 1, 2, 3, or 4 R₆                groups; wherein            -   R₆ at each occurrence is independently selected from the                group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl,                C₁-C₆ alkoxy, CF₃, and OCF₃; and    -   R₅ is -M-G-A, wherein    -   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,        thiophenyl, and pyrrolyl, each of which is substituted with 1,        2, or 3 groups that are independently selected from the group        consisting of F, Cl, Br, C₁-C₄ alkyl, hydroxy, methoxy, ethoxy,        isopropoxy, CF₃, OCF₃, halo C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and        hydroxy C₁-C₄ alkyl;    -   G is selected from a direct bond between M and A, and O; and    -   A is selected from the group consisting of phenyl, naphthyl,        pyridyl, pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl,        isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, and        dihydronaphthyl, wherein each is unsubstituted or substituted        with 1, 2, or 3 groups that are independently selected from the        group consisting of F, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo        C₁-C₄ alkyl, CF₃, OCF₃, CN, and NO₂;    -   with the proviso that when M is phenyl, G is a direct bond        between M and A, and A is phenyl, then at least one of the four        remaining hydrogens on the phenyl ring of M, of M-G-A, must be        substituted with a group independently selected from halogen,        alkyl; hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and        hydroxyalkyl.

In another example, the invention comprises a compound orpharmaceutically acceptable salt thereof of structural formula VIII:

wherein R₃ is selected from:

and R₃ is selected from

In another example, the invention comprises a compound orpharmaceutically acceptable salt thereof listed in Table 1:

TABLE 1 # Compound Name 1N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- argininamide2 N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide 3N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D- argininamide 4N²-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N¹-hydroxy-D- argininamide 5N²-[(3,5-difluoro-4-phenoxyphenyl)sulfonyl]-N¹-hydroxy-D- argininamide 6N²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide 7N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamide 8N²-{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide 9N²-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamide 10N²-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide 11N²-{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide 12N²-{[4-(3,5-dimethylphenoxy)-3-fluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide 13N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide 14N¹-hydroxy-N²-{[6-(5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridin-3-yl]sulfonyl}-D-argininamide 15N⁵-[(Z)-amino(nitroimino)methyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- ornithinamide 16N⁵-[(Z)-amino(nitroimino)methyl]-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-ornithinamide 17N⁶-[(E)-amino(cyanoimino)methyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D-lysinamide 18N⁶-[(E)-amino(cyanoimino)methyl]-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-lysinamide 19N⁶-{(E)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D-lysinamide 20N⁶-{(Z)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N¹-hydroxy-N²-[(4-phenoxyphenyl) sulfonyl]-D-lysinamide 21N⁶-{(Z)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N²-{[4-(4-fluorophenoxy)phenyl] sulfonyl}-N¹-hydroxy-D-lysinamide 22N⁶-[(E)-(cyanoimino)(propylamino)methyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D-lysinamide 23N⁶-[(E)-(cyanoimino)(propylamino)methyl]-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-lysinamide 24N⁶-[(E)-(cyanoimino)(propylamino)methyl]-N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-lysinamide 25N⁶-{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 26N⁶-{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N¹-hydroxy-N²-[(4-phenoxyphenyl) sulfonyl]-D-lysinamide 28N⁶-[(Z)-(cyanoimino)(cyclopropylamino)methyl]-N¹-hydroxy-N²-[(4-phenoxyphenyl) sulfonyl]-D-lysinamide 29N⁶-[(E)-[(aminocarbonyl)imino](hydroxyamino)methyl]-N²-{[4-(4-fluorophenoxy)phenyl] sulfonyl}-N¹-hydroxy-D-lysinamide 30N¹-hydroxy-5-morpholin-4-yl-N²-[(4-phenoxyphenyl)sulfonyl]-D-norvalinamide 31 N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-5-morpholin-4-yl-D-norvalinamide 32N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 33N¹-hydroxy-6-morpholin-4-yl-N²-[(4-phenoxyphenyl)sulfonyl]-D-norleucinamide 34 N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 35N²-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 36N²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 37N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 38N⁶-[(E)-(cyanoimino)(morpholin-4-yl)methyl]-N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-lysinamide 39N⁶-[(Z)-(cyanoimino)(morpholin-4-yl)methyl]-N²-{[3-fluoro-4-(4-fluorophenoxy)pheny]sulfonyl}-N¹-hydroxy-D-lysinamide 403-{1-[amino(imino)methyl]piperidin-4-yl}-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]alaninamide 413-{1-[(Z)-(cyanoimino)(propylamino)methyl]piperidin-4-yl}-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]alaninamide 423-(1-{(Z)-(cyanoimino)[(2-methoxyethyl)amino]methyl}piperidin-4-yl)-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]alaninamide 43 3-(1-{(E)-(cyanoimino)[(2-methoxyethyl)amino]methyl}piperidin-4-yl)-N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxyalaninamide 443-(1-{(Z)-[(aminocarbonyl)imino][(2-methoxyethyl)amino]methyl}piperidin-4-yl)-N¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]alaninamide 45N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide 46N²-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide 47N²-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 48N²-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 49N⁶-4,5-dihydro-1H-imidazol-2-yl-N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-lysinamide 50N⁶-[(Z)-(cyanoimino)(cyclopropylamino)methyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl] sulfonyl}-N¹-hydroxy-D-lysinamide 51N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-3-ylalaninamide 52N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyrrolidin-3-ylalaninamide 53N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide54 N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- tryptophanamide 55N¹-hydroxy-N²-({5-[2-(methylthio)pyrimidin-4-yl]-2-thienyl}sulfonyl)lysinamide 56N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-histidinamide 57N¹-hydroxy-N²-methyl-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-3-ylalaninamide 58N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-4-ylalaninamide 59N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyridin-3-yl-D-alaninamide 60N⁶-glycyl-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 61N¹-hydroxy-N²,N⁶,N⁶-trimethyl-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide 623-[4-(aminomethyl)cyclohexyl]-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}alaninamide 63N¹-hydroxy-N²-{[6-(naphthalen-1-yloxy)pyridin-3-yl]sulfonyl}-D-argininamide 64 N¹-hydroxy-N²-{[6-(5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridin-3-yl]sulfonyl}-D-lysinamide 65N⁶-[(E)-(cyanoimino)(hydroxyamino)methyl]-N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-lysinamide 66N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D- lysinamide 67N⁶-{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 68N²-({6-[(4-fluorophenyl)oxy]pyridin-3-yl}sulfonyl)-N¹-hydroxy-D-argininamide 69N²-({6-[(4-chlorophenyl)oxy]pyridin-3-yl}sulfonyl)-N¹-hydroxy-D-argininamide 70N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-N⁶-(morpholin-4-ylcarbonyl)-D-lysinamide 714-cyano-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-phenylalaninamide 72 4-cyano-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D- phenylalaninamide 733-cyano-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D- phenylalaninamide 743-cyano-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-phenylalaninamide 75N²-({3,5-difluoro-4-[(4-hydroxyphenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyargininamide 76N²-{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N¹-hydroxyargininamide 77N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-N⁶-({[2-(methyloxy)ethyl]amino}carbonyl)-D-lysinamide 78N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N⁶-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]-N¹-hydroxy-D-lysinamide 79 N²-{[3,5-difluoro-4-({4-[(phenylmethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-N¹- hydroxyargininamide80 N²-{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 81N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3-morpholin-4-yl-D-alaninamide 82N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-4-[(hydroxyamino)(imino)methyl]-D-phenylalaninamide 83N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3-[(hydroxyamino)(imino)methyl]-D-phenylalaninamide 84N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[1-(morpholin-4-ylcarbonyl)piperidin-4- yl]alaninamide 85N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3-[1-(morpholin-4-ylcarbonyl)piperidin-4- yl]alaninamide 863-[amino(imino)methyl]-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D- phenylalaninamide 874-[amino(imino)methyl]-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D- phenylalaninamide 88N⁵-(aminocarbonyl)-N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-ornithinamide 89(2R)—N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-4-(dimethylamino)-N¹- hydroxybutanamide90 (2R)—N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-4-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-2-methylbutyl]amino}-N¹- hydroxybutanamide 91N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 92(2R)-4-amino-N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxybutanamide 93(2R)-4-{[amino(imino)methyl]amino}-N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxybutanamide 94 N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4- ylacetamide 95N²-[({4-[(4-chlorophenyl)oxy]-3-fluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide 96N²-[({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide 97N²-[({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide 98N²-({[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}amino)-N¹-hydroxy-2-piperidin-4-ylacetamide 99N²-[({4-[(3,5-dimethylphenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4- ylacetamide 1003-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxyalaninamide 1013-[4-(aminomethyl)cyclohexyl]-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide 1023-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-chlorophenyl)oxy]-3-fluorophenyl}sulfonyl)-N¹-hydroxyalaninamide 1033-[4-(aminomethyl)cyclohexyl]-N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide 1043-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide 1053-[4-(aminomethyl)cyclohexyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxyalaninamide 1063-[4-(aminomethyl)cyclohexyl]-N²-({4-[(3,5-dimethylphenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹- hydroxyalaninamide

In another example, the invention comprises a pharmaceutical compositioncomprising a compound as described in any of paragraphs [0010]-[0038]and a pharmaceutically acceptable carrier.

In another example, the invention comprises a method of making acompound as described in any of paragraphs [0010]-[0038]. In particularare described, methods of making bis-aryl ether sulfonyl halideintermediates, which are used to make compounds of the invention,methods of making compounds of the invention both in solution-phase aswell as on solid-phase.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds of the invention and are intended toapply uniformly throughout the specification and claims unless expresslystated otherwise.

The term alkyl refers inclusively to a univalent C₁ to C₂₀ (unlessexplicitly stated otherwise) saturated straight, branched, cyclic, andcombinations thereof alkane moiety and specifically includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl. In certain instances, specificcycloalkyls are defined (e.g. C₃-C₈ cycloalkyl) to differentiate themfrom generically described alkyls (that, again, are intended to construeinclusion of cycloalkyls). Thus “alkyl” includes, e.g., C₃-C₈cycloalkyl. The term “alkyl” also includes, e.g., C₃-C₈ cycloalkyl C₁-C₆alkyl, which is a C₁-C₆ alkyl having a C₃-C₈ cycloalkyl terminus.Alkyl's can be optionally substituted with any appropriate group,including but not limited to one or more moieties selected from halo,hydroxyl, amino, arylalkyl, heteroarylalkyl, alkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art or as taught, forexample, in Greene, et al., “Protective Groups in Organic Synthesis,”John Wiley and Sons, Second Edition, 1991.

The term alkoxy refers to an alkyl (as defined above) moiety having aterminal —O— with a free valence, e.g., CH₃CH₂—O—;

The term alkenyl refers to a univalent C₂-C₆ straight, branched, or inthe case of C₅₋₈, cyclic hydrocarbon with at least one double bond.

The term aryl refers to a univalent phenyl, biphenyl, napthyl, and thelike. The aryl group can be optionally substituted with any suitablegroup, including but not limited to one or more moieties selected fromhalo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,“Protective Groups in Organic Synthesis,” John Wiley and Sons, SecondEdition, 1991). As well, substitution on an aryl can include fused ringssuch as in tetrahydronaphthalene, chromen-2-one, dibenzofuran, and thelike. In such cases, e.g. tetrahydronaphthalene, the aryl portion of thetetrahydronaphthalene is attached to the portion of a molecule describedas having an aryl group.

The term heteroatom means O, S, or N.

The term heterocycle refers to a cyclic alkyl, alkenyl, or aryl moietyas defined above wherein one or more ring carbon atoms is replaced witha heteroatom.

The term heteroaryl specifically refers to an aryl that includes atleast one of sulfur, oxygen, and nitrogen in the aromatic ring.Non-limiting examples are pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

The term halo refers to chloro, fluoro, iodo, or bromo.

As used herein, the term pharmaceutically acceptable salts or complexesrefers to salts or complexes that retain the desired biological activityof the above-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The term pharmaceutically active derivative refers to any compound thatupon administration to the recipient, is capable of providing directlyor indirectly, the compounds disclosed herein.

In some examples, as will be appreciated by those skilled in the art,two adjacent carbon containing groups on an aromatic system may be fusedtogether to form a ring structure. The fused ring structure may containheteroatoms and may be substituted with one or more substitution groups“R”. It should additionally be noted that for cycloalkyl (i.e. saturatedring structures), each positional carbon may contain two substitutiongroups, e.g. R and R′.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclic ring systems. Forpurposes of this disclosure, it is understood that such imino, amino,oxo or hydroxy substituents may exist in their corresponding tautomericform, i.e., amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are generally named using ACD/Name (availablefrom Advanced Chemistry Development, Inc. of Toronto, Canada). Thissoftware derives names from chemical structures according to systematicapplication of the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC), International Union ofBiochemistry and Molecular Biology (IUBMB), and the Chemical AbstractsService (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. When desired, theR- and S-isomers may be resolved by methods known to one skilled in theart, for example by: formation of diastereoisomeric salts or complexeswhich may be separated, for example, by crystallization; via formationof diastereoisomeric derivatives which may be separated, for example, bycrystallization, gas-liquid or liquid chromatography; selective reactionof one enantiomer with an enantiomer-specific reagent, for exampleenzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, for example on a chiral support, such as silica witha bound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about 1 and about 6 carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about 1 and about 6 carbons). Amides and esters of the compoundsof the present invention may be prepared according to conventionalmethods. A thorough discussion of prodrugs is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; e.g., biotransformation to a more polar molecule such as byoxidation, reduction, or hydrolysis, or to a conjugate (see Goodman andGilman, “The Pharmacological Basis of Therapeutics” 8.sup.th Ed.,Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be synthesized suchthat the biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc. Compositions of the invention may be used incombination with anticancer or other agents that are generallyadministered to a patient being treated for cancer. Adjuvants includepreserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylalted hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated, prophalactically or otherwise.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one skilled in the art.

The compounds of the invention can be made following the teachingsprovided in the Examples, below, and method routine to those of ordinaryskill in the art. The Examples describe how to make sulfonyl chlorideintermediates used to make compounds of the invention, as well assolution and solid-phase methods of making compounds of the invention.The Examples are illustrative and are not intended to be limiting.

EXAMPLES Example 1 Synthesis of Intermediates4-(4-fluorophenoxy)-3,5-difluorophenylsulfonyl Chloride

Step 1: A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol,commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml),4-fluorophenol (13.9 g, 124 mmol), and Cs₂CO₃ (56 g, 172 mmol) wasstirred under N₂ at 60-70° C. for 1-2 hrs. After cooling to roomtemperature, the reaction mixture was partitioned between H₂O and EtOAc.The phases were separated and the aqueous phase was further extractedwith EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×),dried over Na₂SO₄, and concentrated in vacuo to give4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which wasused in the next step without further purification. ¹H NMR (DMSO-d₆): δ7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).

Step 2: A mixture of 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (30.4g, 113 mmol), EtOAc (300 ml), 10% Pd/C (2.6 g) was stirred under anatmosphere of H₂ at room temperature and pressure for approximately 6hrs. The reaction mixture was filtered through Celite and concentratedin vacuo to give 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5 g, 98%)which was used in the next step without further purification. ¹H NMR(CDCl₃): δ 3.82 (s, 2H), 6.26 (d, 2H, J=8.4 Hz), 6.88 (m, 2H), 6.93 (m,2H).

Step 3: A solution of NaNO₂ (8.4 g, 122 mmol) in H₂O (20 ml) was addeddropwise to a mixture of 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5g, 111 mmol), AcOH (160 ml), and conc. HCl (160 ml) cooled in anice/NaCl/H₂O bath. After addition was complete, the mixture was stirredan additional 20-30 minutes before a mixture of SO₂ (74 g, 1.15 mol) inAcOH (140 ml) and CUCl₂-2H₂O (11.1 g, 65 mmol) in H₂O (16 ml) was added.The reaction mixture was removed from the ice bath and stirred at roomtemperature for 1-2 hrs. The reaction mixture was poured into ice waterand extracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extractions werewashed with sat'd NaCl (1×), dried over Na₂SO₄, and concentrated invacuo. The resulting crude oil was purified by flash chromatography (9:1hexanes:EtOAC) to give 4-(4-fluorophenoxy)-3,5-difluorophenylsulfonylchloride (29.8 g, 83%). ¹H NMR (CDCl₃): δ 6.94 (m, 2H), 7.10 (m, 2H),7.71 (d, 2H, J=6.4 Hz).

4-(4-Chlorophenoxy)-3,5-difluorophenylsulfonyl Chloride

Step 1: A mixture of 3,4,5-trifluoronitrobenzene (6.6 g, 37 mmol), dryDMF (30 ml), 4-chlorophenol (5.26 g, 41 mmol), and Cs₂CO₃ (18.8 g, 58mmol) was stirred under N₂ at 60-70 C for 1-2 hrs. After cooling to roomtemperature, the reaction mixture was partitioned between H₂O and EtOAc.The phases were separated and the aqueous phase was further extractedwith EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×),dried over Na₂SO₄, and concentrated in vacuo to give4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (11.3 g, 106%) which wasused in the next step without further purification. ¹H NMR (CDCl₃): δ6.90 (d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=7.6 Hz), 7.94 (d, 2H, J=6.4 Hz).Note: K₂CO₃/acetonitrile can be used in lieu of Cs₂CO₃/DMF.

Step 2: A mixture of 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (10.6g, 37 mmol), toluene (150 ml), H₂O (150 ml), iron powder (6.9 g, 124mmol), and ammonium acetate (9.3 g, 120 mmol) was heated to reflux withstirring for 2-3 hrs. After cooling to room temperature, the reactionmixture was filtered through Celite with thorough washing with H₂O andEtOAc. The filtrate was transferred to a separatory funnel and thephases separated. The aqueous phase was further extracted with EtOAc(2×). The combined organic phases were washed with H₂O (1×), sat'd NaCl(1×), dried over Na₂SO₄, and concentrated in vacuo to give4-(4-chlorophenoxy)-3,5-difluoroaniline (10.8 g, 113%) which was used inthe next step without further purification. ¹H NMR (CDCl₃): δ 3.81 (s,2H), 6.27 (d, 2H, J=9.2 Hz), 6.85 (d, 2H, J=9.2 Hz), 7.21 (d, 2H, J=9.2Hz).

Step 3: A solution of NaNO₂ (2.8 g, 41 mmol) in H₂O (7.0 ml) was addeddropwise to a mixture of 4-(4-chlorophenoxy)-3,5-difluoroaniline (9.5 g,37 mmol), AcOH (50 ml), and conc. HCl (50 ml) cooled in an ice/NaCl/H₂Obath. After addition was complete, the mixture was stirred an additional20-30 minutes before a mixture of SO₂ (25 g, 290 mmol) in AcOH (50 ml)and CuCl₂-2H₂O (3.8 g, 22 mmol) in H₂O (6.0 ml) was added. The reactionmixture was removed from the ice bath and stirred at room temperaturefor 1-2 hrs. The reaction mixture was poured into ice water andextracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extractions were washedwith sat'd NaCl (1×), dried over Na₂SO₄, and concentrated in vacuo. Theresulting crude oil was purified by flash chromatography (9:1hexanes:EtOAC) to give 4-(4-chlorophenoxy)-3,5-difluorophenylsulfonylchloride (11.0 g, 87%). ¹H NMR (CDCl₃): δ 6.92 (d, 2H, J=7.2 Hz), 7.30(d, 2H, J=7.2 Hz), 7.72 (d, 2H, J=4.8 Hz).

3,4,5-trifluorobenzenesulfonyl Chloride

To a 2000 mL round-bottomed flask was added 800 mL distilled H₂O and astir bar. Upon stirring, the flask was cooled to −10° C. in anice-acetone bath. The flask was fitted with a 500 mL addition funnel andSOCl₂ (300 mL, 4.1 mol, 10 eq.) was added dropwise over a period of 1 h.After complete addition, the solution was stirred for 4 h while warmingto room temperature.

Meanwhile, in a separate 500 mL recovery flask was added3,4,5-trifluoroaniline (61 g, 0.41 mol, 1.0 eq.), conc. HCl (150 mL),and a stir bar. The resulting suspension was stirred vigorously andcooled to −10° C. The flask was fitted with a 250 mL addition funnel anda solution of NaNO₂ (34.3 g, 0.50 mol, 1.2 eq.) in H₂O (125 mL) wasadded to the suspension dropwise over a period of 10 min. The reactionmixture, now nearly homogeneous, is yellow-orange in color. The reactionmixture was stirred for an additional 30 min while carefully maintainingthe temperature at −10° C.

The flask containing the SOCl₂/H₂O solution is cooled again to −10° C.and a catalytic amount of Cu(I) Cl (˜50 mg) was added. The solutionturns dark green in color. The flask was fitted with a 500 mL additionfunnel (previously chilled to 0° C.) and the 3,4,5-trifluorodiazobenzenesolution was quickly transferred to the funnel. The solution wasimmediately added dropwise over a period of 3 min. After addition, thereaction mixture slowly turns darker green in color, but after stirringfor 5 min becomes bright, lime green. The reaction was stirred for anadditional hour while warming to room temperature. The reaction mixturewas transferred to a separatory funnel and extracted with CH₂Cl₂ (3×200mL). The organic phases are combined and dried over anhydrous Na₂SO₄,filtered, and concentrated to give a dark-bronze oil (79.5 g, 83%).

Example 2 Synthesis ofN²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamideArginine-Derived Trifluoroarylsulfonamide Intermediate(EXEL-01260235)→Same Compound as in Example 6

To a 1000 mL round-bottomed flask was added H-D-Arg(Pmc)-OH (15.7 g,35.7 mmol, 1.0 eq.), CH₂Cl₂ (250 mL), and a stir bar. The resultingsuspension was stirred vigorously and trimethylsilyl chloride (TMS-Cl)(7.76 g, 71.4 mmol, 2.0 eq.) was added via syringe over a period of 30sec. After stirring for approximately 20 min, the solution becomeshomogeneous. Et₃N (20 mL, 143 mmol, 4.0 eq.) was added via syringe overa period of 1 min. After stirring for an additional 20 min, the reactionflask was fitted with a 250 mL addition funnel and a solution of3,4,5-trifluorobenzenesulfonyl chloride (9.06 g, 39.3 mmol, 1.1 eq.) inCH₂Cl₂ (50 mL) was added dropwise over a period of 3 min. The reactionmixture was stirred overnight at room temperature. The reaction mixturewas then concentrated in vacuo and dissolved in saturated NaHCO₃ (500mL) with stirring. The homogeneous solution was transferred to aseparatory funnel and extracted with Et₂O (2×100 mL). The aqueous phasewas drained into a 2000 mL beaker and acidified to pH 2 with 1 N HCl.Upon acidification, the desired sulfonamide precipitated as a whitesolid (sulfonamide). The aqueous suspension was extracted with EtOAc(2×300 mL). The organic phase was washed with brine (1×100 mL) and theorganic phases were combined and dried over anhydrous NaHCO₃, filtered,and concentrated to give an off-white solid. The solid was purified viaflash chromatography (10% MeOH in CH₂Cl₂ w/0.05% AcOH, R_(f)=0.33),yielding the pure sulfonamide as an off-white solid as a foam (14.5 g,64%). LC/MSD (HP Series 1100 MSD): Expected MW: 634.17, Observed M+H,635.1, Retention time: 1.5 min.

Arginine-Derived Bis-Aryl Ether Intermediate

To a 1000 mL recovery flask was added trifluorobenzene sulfonamide (7.0g, 11.0 mmol, 1.0 eq.), 4-fluorophenol (12.4 g, 110 mmol, 10 eq.), DMSO(230 mL), and a stir bar. With stirring the flask was fitted with a 100mL addition funnel and potassium tert-butoxide (1 M in t-BuOH, 99 ml, 99mmol, 9.0 eq.) was added dropwise over a period of 5 min. Upon completeaddition the reaction flask was heated overnight in an oil bath at 65°C. The reaction color becomes an opaque brown as the reactionprogressed. The reaction mixture was removed from the oil bath, allowedto cool to room temperature, and diluted with EtOAc (300 mL). Themixture was then acidified to pH 2-3 with 1N HCl. The aqueous layer wasextracted with EtOAc (3×50 mL). The organic phases were combined andwashed with brine (1×100 mL). The organic phase was dried over anhydrousNa₂SO₄, filtered, and concentrated to give a dark, viscous oil that wascarried onto the next step without purification. LC/MSD (HP Series 1100MSD): Expected MW: 726.20, Observed M+H, 727.1, Retention time: 1.62min.

Arginine-Derived-Bis-Aryl Ether Intermediate: Ester Formation

To a 200 mL recovery flask was added crude biphenyl ether (˜6.6 g, 9.04mmol, 1.0 eq.) and anhydrous MeOH (125 mL). HCl gas was bubbled into thereaction until the solution was saturated. The reaction was fitted witha septum and stirred overnight at room temperature. The reaction mixturewas concentrated to a viscous oil and purified via flash chromatography(gradient of 100% Hex to 100% EtOAc) to yield a off-white bubbly solid(3.3 g, 49% over two steps from the trifluorobenzene sulfonamide freeacid). LC/MSD (HP Series 1100 MSD): Expected MW: 740.22, Observed M+H,741.1, Retention time: 1.95 min.

Arginine-Derived Bis-Aryl Ether Intermediate: Removal of GuanidineProtecting Group

To a 500 mL recovery flask was added biphenyl ether methyl ester (3.3 g,4.45 mmol, 1.0 eq.) and a stir bar. In a separate Erlenmeyer flask, 60%TFA/CH₂Cl₂ solution (250 mL) was prepared. The solution was added to thereaction flask and the resulting solution was stirred for 1.5 h. Thereaction mixture was concentrated in vacuo and azeotroped with toluene(3×20 mL). The oil was further concentrated under high vacuum to removeresidual toluene and TFA. The resulting oil was carried onto the nextstep with further purification. LC/MSD (HP Series 1100 MSD): ExpectedMW: 474.12, Observed M+H, 475.1, Retention time: 1.45 min.

N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamide

Trifluoroacetate salt ofN-2-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N-1-hydroxy-D-argininamide(EXEL-01260235): Solutions of HONH₂.HCl (6.18 g, 89.0 mmol, 20 eq.) inhot anhydrous MeOH (31 mL) and KOH (7.48 g, 133 mmol, 30.0 eq.) in hotanhydrous MeOH (19 mL) were prepared. Upon dissolving, both solutionswere removed from the hotplate and the KOH solution was added directlyto the HONH₂.HCl solution. Upon addition, a white solid (KCl)immediately precipitated. The resulting solution was allowed to standfor 20 min. The solution was filtered into a 200 mL recovery flaskcontaining the methyl ester (2.1 g, 4.45 mmol, 1.0 eq.) and a stir bar.Considerable bubbling occurred upon addition. The reaction was stirredat room temperature for 1.5 h. The reaction mixture was acidified to pH5 with 1N HCl. A viscous solid formed in the flask. The solution wasconcentrated and then redissolved in MeOH. An off-white solid (HONH₂)remains out of solution. The solution was filtered and concentrated.Filtration was repeated as necessary until no more HONH₂ was evident.The resulting dark solid was redissolved in MeOH and purified viareverse phase HPLC (0.5% TFA/AcCN, 0.5% TFA/H₂O) to give an off-whitesolid (1.0 g, 48% over two steps from Pmc-protected methyl ester).LC/MSD (HP Series 1100 MSD): Expected MW: 475.11, Observed M+H, 476.1,Retention time: 1.33 min.

Example 3 Synthesis ofN²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide(EXEL-01260250)→Same Compound as in Example 5 andN²-{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide(EXEL-01348386)

The above compounds (X=Cl, Br) were prepared via solution phasechemistry in a manner similar to description above:

-   -   N²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide        (EXEL-01260250)LC/MSD (HP Series 1100 MSD): Expected MW: 491.08,        Observed M+H, 492.0, Retention time: 1.37 min    -   N²-{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide        (EXEL-01348386) LC/MSD (HP Series 1100 MSD): Expected MW:        535.03, Observed M+H, 536.0, Retention time: 1.39 min

Example 4N-2-[(3,5-difluoro-4-phenoxyphenyl)sulfonyl]-N-1-hydroxy-D-argininamide(EXEL-01260232)

The above compound was prepared according to solid phase methodsdescribed below. LC/MSD (HP Series 1100 MSD) Expected MW: 457.12,Observed M+H, 458.1 Retention time: 1.38 min.

Example 5 Alternative synthesis ofN-2-([4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl)-N-1-hydroxy-D-argininamide

The following synthetic scheme illustrates how bis-aryl ether sulfonylhalide intermediates, as described above, can be used to make compoundsof the invention. That is, rather than forming a bis-aryl ethersulfonamide from an existing haloaryl sulfonamide, as described above,in this case a bis-aryl ether sulfonyl halide is used to acylate, forexample, an arginine-derived intermediate on its alpha-nitrogen to makethe corresponding sulfonamide. Further steps to convert such bis-arylether sulfonamide intermediates to corresponding compounds of theinvention is also illustrated, specifically regarding alternativeprotection de-protection strategies on route to hydroximate-derivedcompounds of the invention.

Sulfonamide b

D-Arg (pmc)-OH (3.21 g) is suspended in dichloromethane (40 ml) and4-chlorophenoxy-3,5-difluorophenylsulfonyl chloride (2.5 g),triethylamine (4.1 ml) and catalytic amount of DMAP are added. Themixture is stirred at room temperature for 5 hrs. After concentrated thereaction mixture, sat. NaHCO3 (60 ml), water (20 ml) and diethyl ether(80 ml) are added and extracted with ether.

The aqueous phase, after acidifying with 6N HCl, is extracted with ethylacetate. The combined organic phases are washed with brine, dried(MgSO4) and concentrated under reduced pressure to give compound b as awhite solid (5.3 g, 98%). MK830-68: M+1=743.1

Methyl Ester C

Compound b is dissolved in dry MeOH (150 ml) and TMSCl (1.82 ml) isadded. The reaction mixture is stirred under the reflux condition for 2hrs. The reaction mixture is concentrated under reduced pressure to givecompound 3 as a white solid. Purification by column chromatography withEtOAc-Hexane (3:1) gives 2.8 g (54%). MK830-70: M+1=757.1

Guanidine d

Compound c (2.8 g) is treated with 50%-trifluoroacetic acid in DCM (50ml) included triethylsilane (0.5 ml) for 3 hrs. After concentrated thereaction mixture, it was co-evaporated with toluene. The residue isextracted with ether to remove the impurity and gives compound 4 asdark-gray solid (2.1 g, 116%). MK830-73: M+1=491.0

N²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide(EXEL-01260250)

Compound d (2.1 g) is treated with 1.76M hydroxylamine in KOH methanolsolution (preparation: 6.96 g of NH₂OH). HCl is dissolved in MeOH (36ml) and 8.4 g of potassium hydroxide is dissolved in MeOH (21 ml), thenmix together and filtered) for 2 hrs. After neutralizing the reactionmixture with 6N HCl, the reaction mixture is filtered to move the salt.The reaction mixture is concentrated and purified by prep-HPLC.Prep-HPLC conditions: 20% to 70% in 60 min (A: water with 0.1% TFA, B:acetonitrile with 0.1% TFA), ca 25 min RT is desired product.

After lyophilization, the product was triturated with 1N—HCl threetimes, and then with water. White solid 0.87 g (38%). MK 830-80:M+1=492.0. H-NMR (CD3OD, 400 MHz Varian): δ 7.58 (d, J=7.2 Hz, 2H), 7.30(d, J=9.2 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 3.68 (t, 1H), 3.18 (m, 2H),1.70 (m, 3H), 1.59 (m, 1H)

Example 6 Alternative synthesis ofN²-{[3,5-Difluoro-4-(4-Fluorophenoxy)Phenyl]Sulfonyl}-N¹-Hydroxy-D-Argininamide(EXEL-01260235)

This compound was synthesized via a similar route toN¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124)(Example 7) andN²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-D-argininamide(EXEL-01260250):

H-D-Arginine (Pmc)-OMe b′

To a round bottom flask equipped with a magnetic stir bar was addedH-D-Arginine (Pmc)-OH (13.1 g, 29.7 mmol, 1.0 eq.), dry MeOH (300 mL),and trimethyl silyl chloride (TMSCl) (16.2 g, 18.9 ml, 148.8 mmol, 5.0eq.). The reaction was then allowed to stir at rt for a total of 36 hbefore concentrating via rotary evaporation. The viscous oil residue wasthen dissolved in 400 mL of saturated NaHCO₃ and allowed to stir for 10min. The aqueous layer was then extracted three times with ethyl acetate(300 mL). The combined EtOAc layers were then dried with Na₂SO₄,concentrated and dried on high vacuum overnight to give H-D-Arginine(Pmc)-OMe b′ as a white foam (12.4 g, 92% yield): LC/MS Calcd for [M+H]⁺454.0, found 455.1.

Sulfonamide d′

To a round bottom flask equipped with a magnetic stir bar was addedH-D-Arginine (Pmc)-OMe b′ (13.0 g, 27.3 mmol, 1.0 eq.), dry CH₂Cl₂ (200mL), Triethyl amine (TEA) (7.23 g, 9.2 mL, 71.5 mmol, 2.5 eq.), andsulfonyl chloride c′ (9.6 g, 30 mmol, 1.05 eq). The reaction was thenallowed to stir at rt for a total of 3 h. An additional 100 ml of CH₂Cl₂and the organic layer was washed 2× with water (200 mL), 2× with 0.5MHCl, and 2× with brine. The organic layer was dried with Na₂SO₄,concentrated, and the solid was columned using the biotage system withthe eluant being 2:1 hexane/ethyl acetate. Sulfonamide d′ was obtainedas a pale yellow foam (20.5 g, 96% yield): LC/MS Calcd for [M+H]⁺ 740.0,found 741.1.2.

Guanidine e′

To a round bottom flask was added Sulfonamide d′ (20.5 g, 27.7 mmol),1:1 TFA:CH₂Cl₂ (500 mL), and triethyl silane (5.0 mL). The reaction wasallowed to sit at rt for 90 min before concentrating via rotaryevaporation. The residual TFA was then removed via azeotroping withtoluene. The oil was then triturated 3× with ether (125 mL) to givecrude guanidine e′ as a white solid. Guanidine e′ was then dissolved in50 mL of EtOAc, concentrated via rotary evaporation, and trituratedagain 2× with ether (50 mL). Drying of crude guanidine e′ on high vacuumovernight afforded a yellow brown foam, which was then rinsed 2× withether (100 mL), and dried on high vacuum, yielding guanidine e′ as ayellow foam which was taken on crude to the next step. LC/MS Calcd for[M+H]⁺ 474.46, found 475.1.

Hyrochloride salt ofN²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamide(EXEL-01260235)

To a round bottom flask was added the above crude Guanidine e′ (12.1 g,26.7 mmol, 1.0 eq.), and freshly made 1.76 M HONH₂ in MeOH (300 mL, 528mmol, 20 eq.). The reaction was allowed to sit at rt overnight beforefiltering off the precipitate, and concentrating the supernatant to onefourth the original volume. The supernatant was then neutralized to pH7.0 dropwise with neat TFA, concentrated via rotary evaporation, andtriturated with ether (100 mL). The crude material EXEL-01260235 wasthen dissolved in 60 mL of 20:80 acetonitrile:water and purified viathree 20 mL injections on a Varian Prep HPLC system: gradient=15% B to70% B in 40 min where A=100% water, 0.1% TFA, and B=100% acetonitrile,0.1% TFA; flow rate=160 mL/min, fraction size=100 mL. Each fraction wasanalyzed on analytical HPLC, and LC/MS. Pure fractions were combined,lyophilized, HCl exchanged with 1N HCl 3×, and water exchanged 1× togive pureN²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-D-argininamideEXEL-01260235 as a white solid (6.5 g, 45% yield). LC/MS Calcd for[M+H]⁺ 475.44, found 476.1; ¹HNMR (400 MHz, MeOD): δ 7.68 (dt, J=8.8,3.2 Hz, 2H), 7.14 (M, J=8.4 Hz, 6H), 3.65 (t, J=7.6 Hz, 1H), 3.15 (t,J=6.4 Hz, 2H), 1.51-1.69 (m, 4H).

Example 7 Hydrochloride salt ofN-1-Hydroxy-N-2-[(4-Phenoxyphenyl)Sulfonyl]-D-Argininamide(Exel-00987124)

This compound was made via two different pathways as shown below.

Sulfonamide c″

To a round bottom flask equipped with a magnetic stir bar was addedH-D-Arginine (Pmc)-OH (60.0 g, 136.4 mmol, 1.0 eq.), dry CH₂Cl₂ (1000mL), 4-phenoxy benzene sulfonyl chloride (b″) (36.4 g, 136 mmol, 1.0eq.), and triethyl amine (75.0 mL, 542.4 mmol, 4.0 eq.). Trimethyl silylchloride (34.2 mL, 271 mmol, 2.0 eq.) was then dropwise to the stirringreaction. The reaction was then allowed to stir at rt for an additional3 h before concentrating via rotary evaporation. The solid residue wasthen dissolved in 300 mL of saturated NaHCO₃ and 300 mL H₂O. The aqueouslayer was then washed twice with ether (200 mL), acidified with 2N HCl(200 mL), and extracted 3× with EtOAc. The combined EtOAc layers werethen dried with Na₂SO₄, concentrated and dried on high vacuum overnightto give Sulfonamide c″ as a white foam (90.0 g, 98% yield): LC/MS Calcdfor [M+H]⁺ 673.0, found 673.2.

Methyl Ester d″

To a round bottom flask equipped with a magnetic stir bar was addedcrude Sulfonamide c″ (45.0 g, 67.0 mmol, 1.0 eq.), dry MeOH (500 mL),and Trimethyl silyl chloride (13.2 mL, 100 mmol, 1.5 eq.). The reactionwas then refluxed under nitrogen for 4 h, cooled to rt, and concentratedvia rotary evaporation. Water (200 mL) and saturated NaHCO₃ (20 mL) wereadded to the solid residue, and the aqueous layer was extracted 3× withEtOAc (200 mL), dried with Na₂SO₄, concentrated and further dried onhigh vacuum overnight to give Methyl Ester d″ as a pale yellow foam(43.0 g, 93.5% yield): LC/MS Calcd for [M+H]⁺ 687.0, found 687.2.

Guanidine e″

To a round bottom flask was added crude Methyl Ester d″ (32.0 g, 46.6mmol), 1:1 TFA:CH₂Cl₂ (500 mL), and triethyl silane (5.0 mL). Thereaction was allowed to sit at rt for 90 min before concentrating viarotary evaporation. The residual TFA was then removed via azeotropingwith toluene. The oil was then triturated 3× with ether (125 mL) to givecrude guanidine e″ as a white solid. Guanidine e″ was then dissolved in50 mL of EtOAc, concentrated via rotary evaporation, and trituratedagain 2× with ether (50 mL). Drying of crude guanidine e″ on high vacuumovernight afforded a yellow brown foam, which was then rinsed 2× withether (100 mL), and dried on high vacuum, yielding guanidine e″ as ayellow foam which was taken on crude to the next step. LC/MS Calcd for[M+H]⁺ 421.0, found 421.1.

Hydrochloride salt ofN¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124)

To a round bottom flask was added to the above crude Guanidine e″ (19.0g, 45.2 mmol, 1.0 eq.), and freshly made 1.76 M HONH₂ in MeOH (380 mL,668.8 mmol, 14.8 eq.). The reaction was allowed to sit at rt overnightbefore filtering off the precipitate, and concentrating the supernatantto one fourth the original volume. The supernatant was then neutralizedto pH 7.0 dropwise with neat TFA, concentrated via rotary evaporation,and triturated with ether (100 mL). Crude EXEL-00987124 was thendissolved in 60 mL of 20:80 acetonitrile:water and purified via three 20mL injections on a Varian Prep HPLC system: gradient=15% B to 70% B in40 min where A=100% water, 0.1% TFA, and B=100% acetonitrile, 0.1% TFA;flow rate=160 mL/min, fraction size=100 mL. Each fraction was analyzedon analytical HPLC, and LC/MS. Pure fractions were combined,lyophilized, HCl exchanged with 1N HCl 3×, and water exchanged 1× togive pure N-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide as awhite solid (6.8 g, 35.9% yield). Mixed fractions contaminated with asmall impurity were also collected in a separate flask and repurified(2.0 g, 10.5% yield). LC/MS Calcd for [M+H]⁺ 422.0, found 422.1; ¹HNMR(400 MHz, MeOD): δ 7.81 (dt, J=8.8, 3.2 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H),7.22 (t, J=7.4 Hz, 1H), 7.1 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H),3.65 (t, J=7.6 Hz, 1H), 3.15 (t, J=6.4 Hz, 2H), 1.51-1.69 (m, 4H).

Hydroxamic Acid f″

To a round bottom flask was added methyl ester d″ (46.0 g, 61.0 mmol,1.0 eq.) and freshly prepared 1.76 M HONH₂ in MeOH (152.0 mL, 268 mmol,4.0 eq.). The reaction was allowed to sit at rt for 3 h before addinganother 152 mL of 1.76M HONH₂. The reaction was continued for another 4h before quenching with 1N HCl (250 mL) to a pH of 5.0. The methanol wasevaporated and the water was decanted from the residual solid crudeproduct. The crude hydroxamic acid f″ was purified in two batches(approximately 25 g each batch) by dissolving in EtOAc, and dry loadingonto a Biotage FLASH 75L pre-packed cartridge, and eluted with 100%EtOAc to afford pure hydroxamic acid f″ as an orange solid (34.7 g, 75%yield). LC/MS Calcd for [M+H]⁺ 688.0, found 688.2

Hydrochloride Salt ofN²-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124)

To a round bottom flask was added hydroxamic acid f″ (19.7 g, 46.9mmol), 1:1 TFA:CH₂Cl₂ (400 mL), and triethyl silane (4.0 mL). Thereaction was stirred at rt for 90 min, and concentrated via rotaryevaporation. The residual TFA was then removed via azeotroping withtoluene. The oil was then triturated 3× with ether (125 mL) to givecrude 2 EXEL-00987124 as a brown solid. The solid was then dissolved in40 mL of 20:80 acetonitrile:water and purified via two 20 mL injectionson a Varian Prep HPLC system: gradient=15% B to 70% B in 40 min whereA=100% water, 0.1% TFA, and B=100% acetonitrile, 0.1% TFA; flow rate=160mL/min, fraction size=100 mL. Each fraction was analyzed on analyticalHPLC, and LC/MS. Pure fractions were combined, lyophilyzed, HClexchanged with 1N HCl 3×, and water exchanged 1× to give pureN¹-hydroxy-N²-[(4-phenoxyphenyl)sulfonyl]-D-argininamide as a whitesolid (5.2 g, 26.3% yield). Mixed fractions contaminated with a smallimpurity were also collected in a separate flask and repurified (1.4 g,7.2% yield). LC/MS Calcd for [M+H]⁺ 422.0, found 422.1; ¹HNMR (400 MHz,MeOD): δ 7.81 (dt, J=8.8, 3.2 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.22 (t,J=7.4 Hz, 1H), 7.1 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 3.65 (t,J=7.6 Hz, 1H), 3.15 (t, J=6.4 Hz, 2 (m, 4H).

Example 8 General Experimental Procedures for the Synthesis ofCyanoguanidines

Sulfonamide c′″

To a round bottom flask equipped with a magnetic stirrer was addedMethylester a′″ (17.0 mmol, 1.0 eq.), dry CH₂Cl₂ (170 mL), SulfonylChloride b′″ (18.5 mmol, 1.1 eq.), and 2,6-lutidine (42.5 mmol, 2.5eq.). The reaction was stirred at rt for 5 h before quenching with H₂O(100 mL) and saturated NH₄Cl (20 mL). The aqueous layer was extracted 3×with EtOAc (100 mL), and the combined organic layers were dried withNa₂SO₄ before concentrating to give crude sulfonamide c′″ as a clearoil. Trituration with 20:80 EtOAc:Hexanes, followed by drying on highvacuum then affords relatively pure sulfonamide c′″ as a white solidthat can be taken on directly to the next step.

Amine d′″

To a round bottom flask equipped with a magnetic stir bar was addedSulfonamide c′″ (1.14 mmol), dry MeOH (20.0 mL), dry CH₂Cl₂ (3.0 mL) and10% Pd/C (120 mg). The reaction was stirred at rt over an atmosphere ofhydrogen for 5 h before filtering over a pad of celite and rinsing 3×with EtOAc. The washes were combined and concentrated to give crudeamine d′″ as a clear oil which can be taken directly onto the next step.

Cyanoguanidine f′″

To a round bottom flask equipped with a magnetic stir bar was addedamine d′″ (1.14 mmol, 1.0 eq.), dry DMF (6.0 mL), dry triethylamine (6.0mL), thiomethylcyanoguanidine e′″ (1.14 mmol, 1.0 eq.), and AgNO₃ (1.23mmol, 1.1 eq.). The brown slurry was stirred at rt overnight in theabsence of light before filtering out the brown precipitate. Thefiltrate was concentrated and placed on high vacuum to remove anyresidual DMF. Crude cyanoguanidine f′″ was then purified via silica gelchromatography.

Hydroxamic Acid g′″

To a round bottom flask was added cyanoguanidine f′″ (0.47 mmol, 1.0eq.) and freshly prepared 1.76 M HONH₂ (1.9 mmol, 4.0 eq.). The reactionwas stirred at rt for 1 h before adding another 1.0 mL of 1.76 M HONH₂.After stirring for an additional 3 h, the reaction was neutralized to apH of 7.0 with 1N HCl. (Care was taken during the neutralization suchthat the pH was never below 7.0 to prevent cyanoguanidine conversion tothe urea.) Silica gel chromatography then afforded pure hydroxamic acidg′″. Alternatively, hydroxamic acid g′″ can be purified via prep HPLC(solvent system=water/acetonitrile with 0.1% TFA), although fractionscontaining hydroxamic acid g′ must be neutralized with saturated NaHCO₃prior to concentration to prevent hydrolysis of the cyanoguanidine tothe corresponding urea).

In the case where R₂=H:

Cyanoimine i′″

To a round bottom flask equipped with a magnetic stir bar was addedamine d′″ (0.51 mmol, 1.0 eq.), isopropanol (3.0 mL), triethyl amine(0.51 mmol, 1.0 eq.), and diphenyl cyano carbonimidate (0.56 mmol, 1.1eq.). The reaction was stirred at rt overnight, concentrated via rotaryevaporation, and purified via silica gel chromatography.

Cyanoguanidine j′″

To a round bottom flask was added cyanoimine i′″ (0.11 mmol),isopropanol (2.0 mL), and concentrated NH₄OH (1.0 mL). The reaction wasstirred at rt overnight, and concentrated via rotary evaporation toafford crude cyanoguanidine j′″ which can be carried onto the next stepwithout further purification.

Example 9 Preparation of Sulfonamide Hydroxamates on Solid Support

General procedure for the sulfonamide hydroxamate synthesis on solidsupport:

General procedure in solid phase syntheses:

Fmoc Deprotection of Resin Bound N-(Fmoc)Hydroxylanine:

2-Chlorotrityl polystyrene resin functionalized withN-(Fmoc)hydroxylamine (0.2 g, 0.154 mmole) was welling indichloromethane (DCM). The resin was treated with 20% piperidine in DCMfor 1 hr. After filtration the resin was washed with DCM then withmethanol (MeOH) and DCM.

Amino Acid Coupling to O-(Resin)Hydroxylamine:

O-(resin)hydroxylamine (0.154 mmole) was treated with a solution of theappropriate N-(Fmoc) protected amino acid (2 eq.) in dimethylformamide(DMF)-DCM containingHATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumhexafluorophosphate, 2 eq.) and diisopropylethylamine (DIEA, 4 eq.). Theresulting slurry was agitated for 13 hrs. The resin was filtered andwashed with DMF, MeOH, and DC

α-N-Fmoc Deprotection of Resin Bound Amino Acid Hydroxylamine:

O-(resin)hydroxylamine-amino acid (α-N-Fmoc) (0.154 mmole) was treatedwith 20% piperidine in DCM. The resin was agitated for 1 hr thenfiltered, washed with DCM, MeOH and DCM.

Formation of Sulfonamide:

O-(resin)hydroxylamino-amino acid (0.154 mmole) was treated withappropriate sulfonyl chloride (2 eq.) containing 2,6-lutidine (2 eq.) inDCM for 13 hrs. The resin was filtered and washed with DCM, MeOH andDCM.

Compound Release from the Resin:

The α-N-substituted resin bound amino acid sulfonamide hydroxamate wastreated with 20% Trifluoroacetic acid (TFA) containing 2% triethylsilanein DCM for 30 min. The resin filtered and evaporated to dryness thenpurified by semi-prep HPLC.

Following compounds are prepared using method described above:N-2-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N-1-hydroxy-D-argininamide,N-1-hydroxy-N-2-[(4-phenoxyphenyl)sulfonyl]-D-argininamide,N-2-([4-(4-fluorophenoxy)phenyl]sulfonyl)-N-1-hydroxy-D-argininamide,N-2-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N-1-hydroxy-D-argininamide,N-2-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide,N-2-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N-1-hydroxy-D-argininamide,and N-2-(1,1′-biphenyl-4-ylsulfonyl)-N-1-hydroxy-D-argininamide

Example 9 Preparation of Pyridylether Sulfonamide Hydroxamate on SolidSupport Formation of Pyridylarylether-Sulfonamide:

O-(resin)hydroxylamino-amino acid (0.154 mmole) was treated with2-chloropyridyl sulfonyl chloride (2 eq.) containing 2,6-lutidine (2eq.) in DCM for 13 hrs. The resin was filtered and washed with DCM, MeOHand DCM.

Formation of Pyridyl-Aryl Ether:

The α-N-substituted resin bound amino acid sulfonamide hydroxamate wastreated with arylalcohol (10 eq.), cesium carbonate (5 eq.) inN-methylpyrrolidinone (NMP) at 80° C. for 13 hrs. The resin filtered andwashed with DMF, MeOH, water, MeOH and DCM.

Compound Release from the Resin:

The α-N-substituted resin bound amino acid sulfonamide hydroxamate wastreated with 20% Trifluoroacetic acid (TFA) containing 2% triethylsilanein DCM for 30 min. The resin filtered and evaporated to dryness thenpurified by semi-prep HPLC.

Following compounds are prepared using method described above:

-   -   N-1-hydroxy-N-2-([6-(5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridin-3-yl]sulfonyl)-D-argininamide        (EXEL-01284764)    -   Series of Mono-fluoro aryl ether: 3,4-difluorosulfonyl chloride        is used instead of 2-chloropyridyl sulfonyl chloride.

Example 10 Preparation of Pyridylether Sulfonamide Hydroxamate on SolidSupport

Following compounds are prepared using method described above:

-   N-2-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N-1-hydroxy-D-argininamide (4)    (EXEL-01154260)-   N-2-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N-1-hydroxy-D-argininamide (9)    (EXEL-01295474)-   N-2-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (10)    (EXEL-01260233)-   N-2-{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (11)    (EXEL-01295489)-   N-2-{[4-(3,5-dimethylphenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (12)    (EXEL-01284765)

The following, Table 2, provides some physical data for some of thecompounds synthesized. The compound numbers in Table 2 correlate tocompound numbers in Table 1.

TABLE 2 Calculated Retention Time Cmpd # MWt Observed MWt (min.) 1 424.4M + H = 425.1 1.1 HP 2 518.6 M + H = 519.1 1.39 HP 3 536.577 M + H =537.1 1.31 Shimadzu 4 502.2 M + H = 503.1 1.45 HP 5 463.5 M + H = 464.11.25 HP 6 520.578 M + H = 521.1 1.71 Shimadzu 7 460.5 M + H = 461.1 1.35HP 8 521.6 M + H = 522.1 1.35 HP 9 469.4 M + H = 470.0 1.25 HP 10 576.6M + H = 577.1 1.25 HP 11 466.5 M + H = 467.0 1.32 HP 12 573.2 M + H =574.2 1.32 HP 14 512.513 M + H = 513.1 1.32 Shimadzu 15 421.47 M + H =422.1 (100%) 1.15 HP 16 457 M + H = 458 1.28 HP 17 439.46 M + H = 440.1(100%) 1.2 HP 18 473.9 M + H = 474.0 (100%) 1.3 HP 19 439.46 M + H =440.1 (100%) 1.25 HP 20 505.6 M + H = 506.2 1.4 HP 21 548.588 M + H =549.1 1.51 Shimadzu 22 457.12 M + H = 458.1 1.38 HP 23 464 M + H = 4651.25 HP 24 566.57 M + H = 567.1 (100%) 1.4 HP 25 491.89 M + H = 492.1(100%) 1.32 HP 26 467.51 M + H = 468.1 (100%) 1.31 HP 28 405.47 M + H =406.1 (100%) 1.46 HP 29 575.56 M + H = 576 1.22 HP 30 449.52 M + H =450.1 (100%) 1.21 HP 31 476.55 M + H = 477.1 (100%) 1.32 HP 32 535.03M + H = 536.0 1.39 HP 33 467.5 M + H = 468.14 1.793 Shimazu 34 528.6 M +H = 529 1.45 HP 35 466 M + H = 467.1 1.15 HP 36 544.62 M + H = 545 1.59HP 37 598.6 M + H = 599 1.48 HP 38 563.61 M + H = 564.1 (100%) 1.5 HP 39463.54 M + H = 464.2 (100%) 1.32 HP 40 559.6 M + H = 1.44 HP 598.0 (M +K, 100%) 41 576.05 M + H = 1.6 HP 614.0 (M + K, 100%) 42 479.526 M + H =480.1 1.34 Shimadzu 43 562.64 M + H = 563 1.25 HP 44 503.5 M + H = 504.11.37 HP 45 481.538 M + H = 482.1 1.27 HP 46 481.53 M + H = 482.1 (100%)1.23 HP 47 517.519 M + H = 518.1 1.42 Shimadzu 48 533.973 M + H = 534.11.39 HP 49 545.62 M + H = 546.1 (100%) 1.45 HP 50 475.11 M + H = 476.11.33 HP

Table 3 shows proton NMR data for selected compounds:

TABLE 3 Entry Name ¹H-NMR 1N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}- H-NMR; δ (CD3OD): 7.79(d, 2H), D-lysinamide 7.42 (t, 2H), 7.22 (t, 1H), 7.09 (d, 2H), 7.05 (d,2H), 3.63 (t, 1H), 2.87 (t, 2H), 1.57-1.68 (m, 4H), 1.44 (m, 1H), 1.37(m, 1H) 2 N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}- H-NMR; δ(CD3OD): 7.79 (q, 2H), 3-piperidin-3-ylalaninamide 7.42 (t, 2H), 7.22(t, 1H), 7.10 (d, 2H), 7.05 (d, 2H), 3.72 (m, 1H), 3.23-3.47 (m, 2H),2.87 (m, 1H), 2.64 (t, 1H), 1.83-2.01 (m, 3H), 1.17-1.74 (m, 4H) 3N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}- H-NMR; δ (CD3OD): 7.80(d, 2H), 3-pyrrolidin-3-ylalaninamide 7.42 (t, 2H), 7.22 (t, 1H), 7.10(d, 2H), 7.06 (d, 2H), 3.72 (q, 2H), 2.22-2.3 (m, 1H), 1.96-2.18 (m,4H), 1.83 (m, 1H), 1.65 (m, 1H) 4N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹- (CD₃OD) 9.21 (br. s,1H), 9.01 (d, hydroxy-D-lysinamide 1H), 8.24 (dd, 1H), 8.04 (d, 1H),7.92 (dd, 1H), 7.88 (dt, 1H), 7.54 (m, 1H), 7.22 (td, 1H), 3.72 (t, 1H),3.20 (br. q, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.45 (m, 2H) ppm 5N-hydroxy-N-{[4-(phenyloxy)phenyl]sulfonyl}-D- H-NMR; δ (CD3OD): 7.50(d, 2H), tryptophanamide 7.42 (m, 3H), 7.32 (d, 1H), 7.24 (m, 2H), 7.06(m, 2H), 6.99 (s, 1H), 6.94 (t, 1H), 6.76 (d, 1H), 6.64 (d, 1H), 3.84(t, 1H), 3.13 (q, 1H), 2.87 (q, 1H) 6N¹-hydroxy-N²-({5-[2-(methylthio)pyrimidin-4- H-NMR; δ (CD3OD): 8.6 (d,1H), yl]-2-thienyl}sulfonyl)lysinamide 7.9 (d, 1H), 7.6 (d, 1H), 7.58(d, 1H), 3.8 (t, 1H), 2.9 (t, 2H), 2.6 (s, 3H), 1.6-1.75 (m, 4H), 1.5(m, 1H), 1.4 (m, 1H) 7 N-hydroxy-N-{[4-(phenyloxy)phenyl]sulfonyl}-D-H-NMR; δ (CD3OD): 8.78 (s, 1H), histidinamide 7.74 (d, 2H), 7.43 (t,2H), 7.31 (s, 1H), 7.23 (t, 1H), 7.10 (d, 2H), 7.02 (d, 2H), 3.94 (q,1H), 2.96-3.12 (q, 2H) 8 N¹-hydroxy-N²-methyl-N²-{[4- H-NMR; δ (CD3OD):7.75 (m, 2H), (phenyloxy)phenyl]sulfonyl}-3-piperidin-3- 7.42 (m, 2H),7.23 (m, 1H), ylalaninamide 7.01-7.12 (m, 4H), 3.34 (m 1H), 3.30 (s,3H), 2.82-3.00 (m, 3H), 2.63-2.71 (m, 1H), 1.85-2.06 (m, 9H) 9N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}- H-NMR; δ (CD3OD): 7.80(d, 2H), 3-piperidin-4-ylalaninamide 7.43 (t, 2H), 7.22 (t, 1H), 7.10(d, 2H), 7.05 (d, 2H), 3.71 (q, 1H), 3.35 (d, 1H), 2.91 (dt, 2H), 1.89(d, 2H), 1.24-1.76 (m, 6H) 10N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}- H-NMR; δ (CD3OD): 8.71(d, 1H), 3-pyridin-3-yl-D-alaninamide 8.64 (s, 1H), 8.34 (d, 1H), 7.91(q, 1H), 7.79 (d, 1H), 7.69 (d, 2H), 7.43 (t, 2H), 7.23 (t, 1H), 7.10(d, 2H), 7.00 (d, 2H), 3.94 (q, 1H), 3.18 (q, 1H), 3.05 (q, 1H) 11N⁶-glycyl-N¹-hydroxy-N²-{[4- H-NMR; δ (CD3OD): 7.79 (d, 2H),(phenyloxy)phenyl]sulfonyl}-D-lysinamide 7.42 (t, 2H), 7.22 (t, 1H),7.10 (d, 2H), 7.05 (d, 2H), 3.64 (s, 2H), 3.60 (t, 1H), 3.19 (m, 2H),1.60 (m, 2H), 1.48 (m, 2H), 1.34 (m, 2H) 12N¹-hydroxy-N²,N⁶,N⁶-trimethyl-N²-{[4- H-NMR; δ (CD3OD): 7.80 (d, 2H),(phenyloxy)phenyl]sulfonyl}-D-lysinamide 7.42 (m, 2H), 7.22 (t, 1H),6.96-7.10 (m, 4H), 3.66 (t, 1H), 3.30 (m, 2H), 3.11 (s, 9H), 1.75-1.85(m, 2H), 1.69 (q, 2H), 1.36-1.50 (m, 2H) 133-[4-(aminomethyl)cyclohexyl]-N¹-hydroxy-N²- H-NMR; δ (CD3OD): 7.80 (d,2H), {[4-(phenyloxy)phenyl]sulfonyl}alaninamide 7.42 (t, 2H), 7.22 (t,1H), 7.10 (d, 2H), 7.05 (d, 2H), 3.67 (q, 1H), 2.99 (m, 1H), 1.99 (m,2H), 1.79 (m, 2H), 1.54 (t, 1H), 1.35-1.42 (m, 3H), 1.26 (m, 1H), 1.06(q, 1H), 0.96 (q, 1H) 14 N¹-hydroxy-N²-{[6-(naphthalen-1-yloxy)pyridin-H-NMR; δ (CD₃OD): 8.46 (br. d, 1H), 3-yl]sulfonyl}-D-argininamide 8.18(d, 1H), 7.95 (d, 1H), 7.84 (m, 2H), 7.50 (m, 3H), 7.30 (d, 1H), 7.18(d, 1H), 3.54 (br. t, 1H), 3.04 (br. t, 2H), 2.50 (m, 1H), 1.8 (m, 3H)ppm. 17 N⁶-[(E)-(cyanoimino)(hydroxyamino)methyl]-N²- H-NMR; δ (CD3OD):7.78 (d, 2H), ({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹- 7.14 (m,4H), 7.01 (d, 2H), 3.56 (t, hydroxy-D-lysinamide 1H), 1.47 (m, 4H), 1.37(m, 2H), 1.19 (m, 2H) 18N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹- H-NMR; δ (CD3OD): 7.67(d, 2H), hydroxy-D-lysinamide 7.04 (m, 4H), 6.92 (d, 2H), 3.52 (t, 1H),1.53 (m, 4H), 1.38 (m, 2H), 1.25 (m, 2H) 19N⁶-{(Z)-(cyanoimino)[(2-morpholin-4- H-NMR; δ (CD₃OD) 9.01 (br. s, 1H),ylethyl)amino]methyl}-N²-{[6-(3- 8.26 (d, 1H), 8.06 (d, 1H), 7.89 (dd,fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy- 2H), 7.52 (br. q, 1H),7.24 (br. t, 1H), D-lysinamide 3.72 (m, 4H), 3.32 (m, 4H), 3.15 (br. t,2H), 2.52 (m, 6H), 1.3-1.8 (m, 5H) ppm. 20N²-({6-[(4-fluorophenyl)oxy]pyridin-3- H-NMR; δ (CD₃OD) 8.45 (br. s,1H), yl}sulfonyl)-N¹-hydroxy-D-argininamide 8.19 (br s, 1H), 7.20 (m,5H), 3.65 (br. s, 1H), 3.25 (m, 4H), 1.65 (m, 3H) ppm. 21N²-({6-[(4-chlorophenyl)oxy]pyridin-3- H-NMR; δ (CD₃OD) 8.45 (d, 1H),yl}sulfonyl)-N¹-hydroxy-D-argininamide 8.19 (dd, 1H), 7.42 (d, 2H), 7.19(dd, 3H), 3.85 (br. t, 1H), 3.20 (m, 2H), 1.80 (m, 4H) ppm 22N²-({3,5-difluoro-4-[(4- H-NMR; δ (CD3OD): 7.52 (d, 2H),fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy- 6.95 (d, 2H), 6.91 (m,2H), 3.26 m, N⁶-(morpholin-4-ylcarbonyl)-D-lysinamide 5H), 3.22 (4H, m),3.04 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H), 1.25 (m, 2H) 234-cyano-N-hydroxy-N-{[4- H-NMR; δ (CD3OD): 7.4 (m, 4H),(phenyloxy)phenyl]sulfonyl}-D- 7.28 (m, 1H), 7.25 (s, 2H), 7.05 (m,phenylalaninamide 4H), 6.78 (M, 2H), 4.03 (m, 1H), 3.10 (m, 1H), 2.85(m, 1H) 25 3-cyano-N-({3,5-difluoro-4-[(4- H-NMR; δ (CDCl3): 7.1-7.4 (m,6H), fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D- 6.94 (m, 2H), 6.84(m, 2H), 4.2 (m, phenylalaninamide 1H), 3.0-3.3 (m, 2H) 263-cyano-N-hydroxy-N-{[4- H-NMR; δ (CDCl3): 7.42 (m, 2H),(phenyloxy)phenyl]sulfonyl}-D- 7.39 (t, 2H), 7.34 (d, 1H), 7.26 (m, 1H),phenylalaninamide 7.21 (t, 2H), 7.15 (m, 1H), 7.04 (d, 2H), 6.74 (d,2H), 4.1 (m, 1H), 3.2 (m, 1H), 2.9 (m, 1H) 27 N²-({3,5-difluoro-4-[(4-H-NMR; δ (CD3OD): 7.6 (d, 2H), hydroxyphenyl)oxy]phenyl}sulfonyl)-N¹-6.8 (d, 2H), 6.7 (d, 2H), 3.7 (t, 1H), hydroxyargininamide 3.2 (t, 2H),1.6-1.8 (m, 4H) 28 N²-{[3,5-difluoro-4-(pyridin-3- H-NMR; δ (CD3OD): 8.5(s, 1H), yloxy)phenyl]sulfonyl}-N¹-hydroxyargininamide 8.4 (s, 1H), 7.62(d, 2H), 7.5 (m, 2H), 3.7 (t, 1H), 3.2 (t, 2H), 1.7 (m, 4H) 30N²-({3,5-difluoro-4-[(4- H-NMR; δ (CD₃OD) 7.60 (d, 2H),fluorophenyl)oxy]phenyl}sulfonyl)-N⁶-[1-(4,4- 7.05 (m, 4H), 3.65 (t,1H), 3.45 (t, dimethyl-2,6-dioxocyclohexylidene)ethyl]-N¹- 1H), 2.60 (s,3H), 2.40 (s, 3H), hydroxy-D-lysinamide 1.65 (m, 4H), 1.45 (m, 3H), 1.0(s, 4H) ppm 31 N²-{[3,5-difluoro-4-({4- H-NMR; δ (CD3OD): 7.6 (d, 2H),[(phenylmethyl)oxy]phenyl}oxy)phenyl]sulfonyl}- 7.4 (d, 2H), 7.35 (m,2H), 6.9 (s, 5H), N¹-hydroxyargininamide 5.02 (s, 2H), 3.65 (t, 1H), 3.1(t, 2H), 1.7 (m, 4H) 32 N²-{[3,5-difluoro-4-(pyridin-3- H-NMR; δ(CD3OD): 1.3-1.5 (m, 2H), yloxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-1.5-1.7 (m, 4H), 1.99 (s, 3H), 4-yl-D-norleucinamide 2.57 (t, 2H), 2.70(br s, 4H), 3.68 (t, 1H), 3.76 (t, 4H), 7.43 (d, 1H), 7.63 (d, 2H), 8.33(dd, 1H), 8.42 (d, 1H 33 N²-({3-fluoro-4-[(4- H-NMR; δ (CD₃OD): 7.70 (m,2H), fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3- 7.10 (m, 5H), 3.80(br. t, 2H), morpholin-4-yl-D-alaninamide 3.20 (m, 6H) ppm 34N-({3,5-difluoro-4-[(4- H-NMR; δ (CD₃OD): 7.61 (d, 2H),fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-4- 7.49 (m, 4H), 7.01 (m,4H), 3.90 (dd, [(hydroxyamino)(imino)methyl]-D- 1H), 3.00 (m, 2H) ppmphenylalaninamide 36 N-({3,5-difluoro-4-[(4- H-NMR; δ (CD₃OD): 7.54 (m,6H), fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-3- 7.02 (m, 4H), 3.94(t, 1H), 3.01 (m, [(hydroxyamino)(imino)methyl]-D- 2H) ppmphenylalaninamide 37 N²-({4-[(4-chlorophenyl)oxy]-3,5- H-NMR; δ (CDCl3):7.54 (d, 2H), difluorophenyl}sulfonyl)-N¹-hydroxy-3-[1- 7.23 (d, 2H),6.85 (d, 2H), 3.98 (m, (morpholin-4-ylcarbonyl)piperidin-4- 1H), 3.63(br, 4H), 3.21 (br, 2H), yl]alaninamide 2.81 (m, 1H), 2.66 (m, 1H), 1.60(br, 2H), 1.10 (m, 1H) 38 N²-({3,5-difluoro-4-[(4- H-NMR; δ (DMSO-d6):10.65 (s, 1H), fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3- 8.45 (d,1H), 7.62 (d, 2H), 7.18 (d, 2H), [1-(morpholin-4-ylcarbonyl)piperidin-4-7.10 (d, 2H), 3.64 (m, 1H), 3.54 (m, yl]alaninamide 4H), 3.08 (m, 2H),2.63 (m, 1H), 2.49 (m, 1H), 1.53 (m, 1H), 1.38 (m, 1H), 1.0 (m, 1H) 393-[amino(imino)methyl]-N-({3,5-difluoro-4-[(4- H-NMR; δ (CD₃OD): 7.58(m, 6H), fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D- 6.99 (m, 4H),3.88 (t, 1H), 3.01 (m, phenylalaninamide 2H) ppm 404-[amino(imino)methyl]-N-({3,5-difluoro-4-[(4- H-NMR; δ (CD₃OD): 7.75(d, 2H), fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D- 7.50 (d, 4H),7.01 (m, 4H), 3.90 (dd, phenylalaninamide 1H), 3.05 (m, 2H) ppm. 41N⁵-(aminocarbonyl)-N~2~-({3-fluoro-4-[(4- H-NMR; δ (CD₃OD): 7.65 (d,1H), fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy- 7.60 (d, 1H), 7.10(m, 5H), 3.82 (t, D-ornithinamide 1H), 3.05 (m, 2H), 1.60 (m, 4H) ppm 42(2R)-2-[({4-[(4-chlorophenyl)oxy]-3,5- H-NMR; δ (CD3OD): 1.97 (q, 2H),difluorophenyl}sulfonyl)amino]-4- 2.11 (q, 2H), 2.78 (s, 6H), 3.71 (t,1H), (dimethylamino)-N-hydroxybutanamide 6.90 (dd, 2H), 7.21 (d, 2H),7.51 (dd, 2H) 43 (2R)-2-[({4-[(4-chlorophenyl)oxy]-3,5- H-NMR; δ(CD3OD): 7.61 (d, 2H), difluorophenyl}sulfonyl)amino]-4-{[1-(4,4- 7.31(d, 2H), 7.00 (d, 2H), 3.77 (t, 1H),dimethyl-2,6-dioxocyclohexylidene)-2- 3.64 (t, 2H), 3.04 (d, 2H), 2.38(s, 4H), methylbutyl]amino}-N-hydroxybutanamide 1.97 (m, 3H), 0.99-1.02(m, 12H) 44 N²-({4-[(4-chlorophenyl)oxy]-3,5- H-NMR; δ (CD₃OD): 7.60 (d,2H), difluorophenyl}sulfonyl)-N¹-hydroxy-3-[(2- 7.30 (m, 2H), 7.00 (d,2H), 3.80 (m, morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 10H), 1.40(d, 6H) ppm 45 (2R)-4-amino-2-[({4-[(4-chlorophenyl)oxy]-3,5- H-NMR; δ(CD3OD): 7.62 (d, 2H), difluorophenyl}sulfonyl)amino]-N- 7.32 (d, 2H),7.01 (d, 2H), 3.79 (t, 1H), hydroxybutanamide 3.08 (m, 1H), 2.98 (m,1H), 1.99 (q, 2H) 46 (2R)-4-{[(amino(imino)methyl]amino}-2-[({4-[(4-H-NMR; δ (CD3OD): 7.61 (d, 2H), chlorophenyl)oxy]-3,5- 7.32 (d, 2H),7.00 (d, 2H), 3.80 (t, 1H), difluorophenyl}sulfonyl)amino]-N- 3.10 (m,1H), 2.98 (m, 1H), 2.00 (q, hydroxybutanamide 2H)

Example 11 Enzyme Assays

mADAM-10 or hADAM-10 activity was measured as the ability to cleave a10-residue peptide(DABCYL-Leu-Leu-Ala-Gln-Lys-*-Leu-Arg-Ser-Ser-Arg-EDANS). This peptideis based on the TNF-α cleavage site (Leu⁶²-Arg⁷¹), however, we foundthat replacement of Ala⁷⁶-Val⁷⁷ with Lys-Leu resulted in a peptide witha 5-fold greater affinity for ADAM-10 than the native TNF-α peptide.Enzyme was diluted to a final active concentration of 5 nM in Buffer A(50 mM HEPES 8.0, 100 mM NaCl, 1 mM CaCl2 and 0.01% NP-40). Serialdilutions for compounds were performed ranging from 100 uM to 0.5 nMusing a Beckman Biomek 2000 in polypropylene plates (Greiner). 20 •l ofenzyme solution was added to 10 •l of compound in buffer A, and allowedto incubate for 15 min in 384 well black, Greiner, microtiter plates(#781076). 20 ul of substrate (12.5 uM in Buffer A) was then added,resulting in final reaction conditions of 2 nM ADAM-10, 5 •M substrate,and compound concentrations ranging from 20 uM to 0.1 nM. The reactionwas incubated for 2 hr at RT, and fluorescence was measured at Ex355,Em460 on a Wallac Victor 2 fluorescence reader. For final analysis ofpotent inhibitors, a similar reaction was set up with a final activeADAM-10 concentration of 0.1 nM. This reaction was incubated for 16 hrat RT and fluorescence was read using identical conditions.

Table 4 below shows structure activity relationship data for selectedcompounds of the invention when tested in vitro with variousmetalloproteases. Inhibition is indicated as IC₅₀ with the followingkey: A=IC₅₀ less than 50 nM, B=IC₅₀ greater than 50 nM, but less than1000 nM, C═IC₅₀ greater than 50 nM, but less than 20,000 mM, and D=IC₅₀greater than 20,000 mM.

One aspect of the invention is the combination of, for example,guanidine-containing sidechains on an amino acid derived hydroximate;and substitution (particularly halo, more particularly fluoro) on theproximal ring (ring bonded directly to the sulfonamide moiety) of atwo-ring-substituted sulfonamide derivative of the amino acid derivedhydroximate. For example, by combining an arginine-derived hydroximatehaving a bis-aryl ether sulfonamide on the alpha-nitrogen, particularlywhen the proximal ring of the bis-aryl ether is substituted with, forexample at least one fluorine, inhibitors that are selective for ADAM-10are produced.

TABLE 4 ADAM-10 MMP1 MMP2 MMP3 MMP8 MMP9 MMP13 TACE # Compound Name IC₅₀IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ 1 N¹-hydroxy-N²-{[4- A B C A A B(phenyloxy)phenyl]sulfonyl}-D- lysinamide 2 N¹-hydroxy-N²-{[4- A C A B AA A B (phenyloxy)phenyl]sulfonyl}-D- argininamide 3 N¹-hydroxy-N²-{[4- AB A A A A (phenyloxy)phenyl]sulfonyl}-3- piperidin-3-ylalaninamide 4N¹-hydroxy-N²-{[4- A B A A A C (phenyloxy)phenyl]sulfonyl}-3-pyrrolidin-3-ylalaninamide 5 N²-{[6-(3-fluorophenyl)pyridin- A C A B A C3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 6 N-hydroxy-N-{[4- A B A A A A(phenyloxy)phenyl]sulfonyl}-D- tryptophanamide 7 N¹-hydroxy-N²-({5-[2- BD A C A C (methylthio)pyrimidin-4-yl]-2- thienyl}sulfonyl)lysinamide 8N-hydroxy-N-{[4- A B A A A B (phenyloxy)phenyl]sulfonyl}-D-histidinamide 9 N¹-hydroxy-N²-methyl-N²-{[4- A B A A A B(phenyloxy)phenyl]sulfonyl}-3- piperidin-3-ylalaninamide 10N¹-hydroxy-N²-{[4- A B A A A B (phenyloxy)phenyl]sulfonyl}-3-piperidin-4-ylalaninamide 11 N¹-hydroxy-N²-{[4- A D A A A A(phenyloxy)phenyl]sulfonyl}-3- pyridin-3-yl-D-alaninamide 12N¹-hydroxy-6-morpholin-4-yl-N²- A B A A A C{[4-(phenyloxy)phenyl]sulfonyl}- D-norleucinamide 13N⁶-glycyl-N¹-hydroxy-N²-{[4- A A A B (phenyloxy)phenyl]sulfonyl}-D-lysinamide 14 N²-{[6-(3-fluorophenyl)pyridin- A B A B A C3-yl]sulfonyl}-N¹-hydroxy-D- argininamide 15N¹-hydroxy-N²,N⁶,N⁶-trimethyl-N²- A B A A A B{[4-(phenyloxy)phenyl]sulfonyl}- D-lysinamide 163-[4-(aminomethyl)cyclohexyl]- A B A A A B N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}alaninamide 17N²-{[6-(3-fluorophenyl)pyridin- A D A B A C 3-yl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 18 N⁶-[(E)- A C A B A C(cyanoimino)(propylamino)methyl]- N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 19N¹-hydroxy-5-morpholin-4-yl-N²- A B A A A A{[4-(phenyloxy)phenyl]sulfonyl}- D-norvalinamide 20 N⁶-[(E)- A C A B A Bamino(cyanoimino)methyl]-N²-{[6- (3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 21N¹-hydroxy-N²-{[6-(naphthalen-1- B C B C Ayloxy)pyridin-3-yl]sulfonyl}-D- argininamide 22 N²-{[3-fluoro-4- A B A AA B (phenyloxy)phenyl]sulfonyl}-N¹- hydroxy-D-argininamide 23 N⁶-[(E)- AB A A A A (cyanoimino)(propylamino)methyl]- N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 24 N⁶-((Z)-(cyanoimino){[2- AB A A A B (methyloxy)ethyl]amino}methyl)- N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 25 N⁶-[(E)- A B A A A Aamino(cyanoimino)methyl]-N¹- hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 26 N²-({4-[(4- A B A A A Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-argininamide 27 N⁵-[(Z)-A B A A A A amino(nitroimino)methyl]-N¹- hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- ornithinamide 28N¹-hydroxy-N~2~-{[6-(5,6,7,8- D B A tetrahydronaphthalen-2-yloxy)pyridin-3-yl]sulfonyl}-D- lysinamide 29 N⁶-{(Z)-(cyanoimino)[(2- AB A A A morpholin-4- ylethyl)amino]methyl}-N¹- hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 30 N⁶-[(Z)- A A A A A(cyanoimino)(cyclopropylamino)methyl]- N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D- lysinamide 31 N²-{[3,5-difluoro-4- A B(phenyloxy)phenyl]sulfonyl}-N¹- hydroxy-D-argininamide 32N²-({4-[(4-chlorophenyl)oxy]-3- A B A A A A fluorophenyl}sulfonyl)-N¹-hydroxy-D-argininamide 33 N²-({3,5-difluoro-4-[(4- A D C C B B A Bfluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-argininamide 343-[1-((Z)-(cyanoimino){[2- B A A(methyloxy)ethyl]amino}methyl)piperidin- 4-yl]-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}alaninamide 35 3-{1-[(Z)- A B A(cyanoimino)(propylamino)methyl] piperidin-4-yl}-N¹-hydroxy-N²- {[4-(phenyloxy)phenyl]sulfonyl}alaninamide 36 N⁵-[(Z)- A B A B A Bamino(nitroimino)methyl]-N²-{[6- (3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- ornithinamide 37N²-({4-[(4-chlorophenyl)oxy]- A C A B B B A B3,5-difluorophenyl}sulfonyl)-N¹- hydroxy-D-argininamide 38N¹-hydroxy-N²-{[6-(5,6,7,8- A C A A A B tetrahydronaphthalen-2-yloxy)pyridin-3-yl]sulfonyl}-D- argininamide 39 N²-({4-[(3,5- A C A B AA dimethylphenyl)oxy]-3- fluorophenyl}sulfonyl)-N¹-hydroxy-D-argininamide 40 N²-({3-fluoro-4-[(4- A B A A A Bfluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-argininamide 41N²-({4-[(4-cyanophenyl)oxy]-3- A C A A A fluorophenyl}sulfonyl)-N¹-hydroxy-D-argininamide 42 N⁶-[(E)-(cyanoimino)(morpholin- A A A A4-yl)methyl]-N²-({4-[(4- fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-lysinamide 43 3-[1-((Z)- A B A A A[(aminocarbonyl)imino]{[2- (methyloxy)ethyl]amino}methyl)piperidin-4-yl]-N¹-hydroxy-N²-{[4- (phenyloxy)phenyl]sulfonyl}alaninamide 44N⁶-(4,5-dihydro-1H-imidazol-2- A A A A A yl)-N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 45 N⁶-[(E)- AB A A A (cyanoimino)(propylamino)methyl]- N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 46 N⁶-[(E)- AA A A [(aminocarbonyl)imino](hydroxyamino) methyl]-N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 47 N⁶-[(E)- AB A A A (cyanoimino)(hydroxyamino)methyl]- N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 48N⁶-((E)-(cyanoimino){[2- A B A A A (methyloxy)ethyl]amino}methyl)-N²-{[6-(3-fluorophenyl)pyridin- 3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide49 N⁶-[(Z)- A D A B A (cyanoimino)(cyclopropylamino)methyl]- N²-{[6-(3-fluorophenyl)pyridin-3- yl]sulfonyl}-N¹-hydroxy-D- lysinamide 50N²-({4-[(4- A B A A A fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-lysinamide 51 N⁶-((Z)-(cyanoimino){[2- A B A A A(methyloxy)ethyl]amino}methyl)- N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 52N⁶-{(Z)-(cyanoimino)[(2- A B A A A morpholin-4-ylethyl)amino]methyl}-N²-{[6-(3- fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D- lysinamide 53 3-{1- A B A A A B[amino(imino)methyl]piperidin-4- yl}-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}alaninamide 54 N²-({4-[(4- A B A A Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-5-morpholin-4-ylnorvalinamide 55 N²-({4-[(4- A B A A A Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide 56 N²-({3,5-difluoro-4-[(4- B C B B Bfluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide 57 N²-({6-[(4- A B A A Afluorophenyl)oxy]pyridin-3- yl}sulfonyl)-N¹-hydroxy-D- argininamide 58N²-({3,5-difluoro-4-[(4- A D A B A fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-6-morpholin-4-yl-D- norleucinamide 59N⁶-[(Z)-(cyanoimino)(morpholin- A B A A A 4-yl)methyl]-N²-({3-fluoro-4-[(4- fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-lysinamide 603-[1-((E)-(cyanoimino){[2- B C A B A(methyloxy)ethyl]amino}methyl)piperidin- 4-yl]-N²-({3,5-difluoro- 4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxyalaninamide 61 N²-({6-[(4-A B A A A chlorophenyl)oxy]pyridin-3- yl}sulfonyl)-N¹-hydroxy-D-argininamide 62 N²-({3,5-difluoro-4-[(4- A C A B Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-N⁶-(morpholin-4-ylcarbonyl)-D-lysinamide 63 4-cyano-N-hydroxy-N-{[4- A B A A A(phenyloxy)phenyl]sulfonyl}-D- phenylalaninamide 644-cyano-N-({3,5-difluoro-4-[(4- B B fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D-phenylalaninamide 65 N²-({4-[(4-chlorophenyl)oxy]- A C A B A3,5-difluorophenyl}sulfonyl)-N¹- hydroxy-6-morpholin-4-yl-D-norleucinamide 66 3-cyano-N-({3,5-difluoro-4-[(4- B C B C Bfluorophenyl)oxy]phenyl}sulfonyl)- N-hydroxy-D-phenylalaninamide 673-cyano-N-hydroxy-N-{[4- A B A A A (phenyloxy)phenyl]sulfonyl}-D-phenylalaninamide 68 N²-{[3-fluoro-4- A C A B A(phenyloxy)phenyl]sulfonyl}-N¹- hydroxy-6-morpholin-4-yl-D-norleucinamide 69 N²-({3,5-difluoro-4-[(4- A D A B Ahydroxyphenyl)oxy]phenyl}sulfonyl)- N¹-hydroxyargininamide 70N²-{[3,5-difluoro-4-(pyridin-3- B D B D C yloxy)phenyl]sulfonyl}-N¹-hydroxyargininamide 71 N²-({3,5-difluoro-4-[(4- A C A Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-N⁶-({[2-(methyloxy)ethyl]amino}carbonyl)- D-lysinamide 72N²-({3,5-difluoro-4-[(4- B C A B A fluorophenyl)oxy]phenyl}sulfonyl)-N⁶-[1-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl]-N¹-hydroxy-D-lysinamide 73 N²-{[3,5-difluoro-4-({4- A D A B A[(phenylmethyl)oxy]phenyl}oxy)phenyl] sulfonyl}-N¹- hydroxyargininamide74 N²-({3-fluoro-4-[(4- B B A B A fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3-[(2-morpholin-4- ylethyl)thio]-D-valinamide 75N²-({4-[(4-bromophenyl)oxy]-3,5- A C A B A difluorophenyl}sulfonyl)-N¹-hydroxy-D-argininamide 76 N²-({3-fluoro-4-[(4- A B A A Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 77 N²-({3-fluoro-4-[(4- B C A B Afluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-3-morpholin-4-yl-D-alaninamide 78 N-({3,5-difluoro-4-[(4- D B C Bfluorophenyl)oxy]phenyl}sulfonyl)- N-hydroxy-4-[(hydroxyamino)(imino)methyl]-D- phenylalaninamide 79N-({3,5-difluoro-4-[(4- A C A C B fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-3- [(hydroxyamino)(imino)methyl]-D- phenylalaninamide 80N²-({4-[(4-chlorophenyl)oxy]- A D A C B 3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[1-(morpholin-4- ylcarbonyl)piperidin-4- yl]alaninamide 813-[amino(imino)methyl]-N-({3,5- A D A C B difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N-hydroxy-D-phenylalaninamide 824-[amino(imino)methyl]-N-({3,5- A D B C B difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N-hydroxy-D-phenylalaninamide 83N⁵-(aminocarbonyl)-N²-({3-fluoro- A B A A A 4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxy-D-ornithinamide 84(2R)-2-[({4-[(4- B A C B chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]- 4-(dimethylamino)-N- hydroxybutanamide85 (2R)-2-[({4-[(4- B D B C B chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]- 4-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-2- methylbutyl]amino}-N- hydroxybutanamide 86N²-({4-[(4-chlorophenyl)oxy]- B C B C B 3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[(2-morpholin-4-yl-2- oxoethyl)thio]-D-valinamide 87(2R)-4-amino-2-[({4-[(4- A C A C A chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]- N-hydroxybutanamide 88 (2R)-4- A C A C A{[amino(imino)methyl]amino}-2- [({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]- N-hydroxybutanamide 892-[({4-[(4-chlorophenyl)oxy]- A A C B 3,5-difluorophenyl}sulfonyl)amino]- N-hydroxy-2-piperidin-4- ylacetamide 902-[({4-[(4-chlorophenyl)oxy]-3- A A B A fluorophenyl}sulfonyl)amino]-N-hydroxy-2-piperidin-4- ylacetamide 91 2-[({3-fluoro-4-[(4- B A B Afluorophenyl)oxy]phenyl}sulfonyl) amino]-N-hydroxy-2-piperidin-4-ylacetamide 92 2-[({4-[(4- A A B A fluorophenyl)oxy]phenyl}sulfonyl)amino]-N-hydroxy-2-piperidin-4- ylacetamide 932-({[6-(3-fluorophenyl)pyridin- B 3-yl]sulfonyl}amino)-N-hydroxy-2-piperidin-4-ylacetamide 94 2-[({4-[(3,5- B C C Cdimethylphenyl)oxy]-3,5- difluorophenyl}sulfonyl)amino]-N-hydroxy-2-piperidin-4- ylacetamide 95 3-[4-(aminomethyl)cyclohexyl]- BB C A N²-({4-[(4-chlorophenyl)oxy]- 3,5-difluorophenyl}sulfonyl)-N¹-hydroxyalaninamide 96 3-[4-(aminomethyl)cyclohexyl]- A B C BN²-({3,5-difluoro-4-[(4- fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide 97 3-[4-(aminomethyl)cyclohexyl]- A A A AN²-({4-[(4-chlorophenyl)oxy]-3- fluorophenyl}sulfonyl)-N¹-hydroxyalaninamide 98 3-[4-(aminomethyl)cyclohexyl]- A C A A AN²-({3-fluoro-4-[(4- fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide 99 3-[4-(aminomethyl)cyclohexyl]- A A A AN²-({4-[(4- fluorophenyl)oxy]phenyl}sulfonyl)- N¹-hydroxyalaninamide 1003-[4-(aminomethyl)cyclohexyl]- A A B A N²-{[(6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹- hydroxyalaninamide 101 3-[4-(aminomethyl)cyclohexyl]-C N²-({4-[(3,5- dimethylphenyl)oxy]-3,5- difluorophenyl}sulfonyl)-N¹-hydroxyalaninamide

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom hydrogen, alkyl, alkanoyl, arylalkyl, and arylalkanoyl, wherein thearylalkyl and arylalkanoyl groups are unsubstituted or substituted with1, 2, 3, 4, or 5 R₆ groups; R₆ at each occurrence is independentlyselected from halogen, hydroxy, —NO₂, —CO₂R₁₀, —CN, alkyl, alkoxy,haloalkyl, and haloalkoxy; R₂ is selected from hydrogen, alkyl, alkoxy,alkanoyl, arylalkyl and arylalkanoyl, wherein the arylalkyl andarylalkanoyl groups are unsubstituted or substituted with 1, 2, 3, 4, or5 R₆ groups; R₃ is -Z-Q-J, wherein Z is selected from alkyl,alkoxyalkyl, alkylthioalkyl, and alkenyl, each of which is unsubstitutedor substituted with 1 or 2 groups that are independently selected fromalkoxy, hydroxy, and halogen; Q is selected from a direct bond between Zand J, —C(═O)—, aryl, heteroaryl, and heterocycloalkyl, wherein thearyl, heteroaryl, or heterocycloalkyl group is unsubstituted orsubstituted with 1 or 2 groups that are independently selected fromalkyl, halogen, —NR₈R₉, and alkoxy; J is selected from —NR₈R₉,—NR₇C(═O)NR₈R₉, —NR₇C(═O)alkylNR₈R₉, —NR₇C(═O)OR₉, —C(═NR₇)NR₈R₉, and—NH—C(═NR₇)NR₈R, wherein R₇ is selected from H, CN, NO₂, alkyl,alkanoyl, arylalkanoyl and —C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ areindependently selected from H, and alkyl, and R₈ and R₉ areindependently selected from H, alkyl, hydroxy, alkoxy, alkoxyalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups;or R₈ and R₉ and the nitrogen to which they are attached form a 5, 6 or7 membered heterocycloalkyl ring, which is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently selected from alkyl,alkoxy, hydroxy, and halogen; or R₇, R₈, and the nitrogens to which theyare attached form a 5, 6 or 7 membered heterocycloalkyl group that isunsubstituted or substituted with 1, 2 or 3 groups that areindependently selected from alkyl, alkoxy, hydroxy, and halogen; and R₉is selected from H, alkyl, hydroxy, alkoxy, alkoxyalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups;R₄ is selected from H, alkyl, and arylalkyl, wherein the arylalkyl groupis unsubstituted or substituted with 1, 2, 3, 4, or 5 R₆ groups; and R₅is -M-G-A, wherein M is aryl and A is heteroaryl, or M is heteroaryl andA is aryl, wherein M is unsubstituted or substituted with 1, 2, 3, or 4groups that are independently selected from halogen, alkyl, hydroxy,alkoxy, haloalkyl, —CN, haloalkoxy, and hydroxyalkyl, and wherein A isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently selected from halogen, alkyl, alkoxy, haloalkyl, aryloxy,heteroaryloxy, arylalkoxy, heteroarylalkoxy, haloalkoxy, —CN, and NO₂; Gis selected from a direct bond between M and A, CH₂, -alkyl-O—,—O-alkyl-, O, S, SO, and SO₂; with the proviso that when M is phenyl, Gis a direct bond between M and A, and A is phenyl, then at least one ofthe four remaining hydrogens on the phenyl ring of M, of M-G-A, must besubstituted with a group independently selected from halogen, alkyl,hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and hydroxyalkyl.
 2. Thecompound according to claim 1, wherein R₁ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, and phenylC₁-C₆ alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 R₆ groups, and R₂ isselected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆alkanoyl, phenyl C₁-C₆ alkyl and phenyl C₁-C₆ alkanoyl, wherein thephenylalkyl and phenylalkanoyl groups are unsubstituted or substitutedwith 1, 2, 3, 4, or 5 R₆ groups, wherein R₆ at each occurrence isindependently selected from the group consisting of halogen, hydroxy,—NO₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.
 3. The compoundaccording to claim 1, wherein R₃ is -Z-Q-J, wherein Z is a C₁-C₆ alkyl,C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆ alkylthio C₁-C₆ alkyl, each of whichis unsubstituted or substituted with 1 or 2 groups independentlyselected from C₁-C₄ alkyl, halogen, and C₁-C₄ alkoxy; Q is a direct bondbetween Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl,imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanylwherein each is unsubstituted or substituted with 1 or 2 groups that areindependently selected from C₁-C₄ alkyl, halogen, and C₁-C₄ alkoxy; J is—C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein R₇ is selected from the groupconsisting of H, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆alkanoyl and —C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ are independentlyselected from H and C₁-C₆ alkyl, R₈ and R₉ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl,thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C₁-C₆alkyl, pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, andpyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl,pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, and furyl C₁-C₆ alkyl,wherein each of the above is unsubstituted or substituted with 1, 2, 3,or 4 R₆ groups; or R₈ and R₉ and the nitrogen to which they are attachedform a 5, 6 or 7 membered heterocycloalkyl ring, which is unsubstitutedor substituted with 1, 2, or 3 groups that are independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, and halogen; or R₇, R₈, and thenitrogens to which they are attached form a 5, 6 or 7 memberedheterocycloalkyl group that is unsubstituted or substituted with 1, 2 or3 groups that are independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, and halogen; and R₉ is selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₃-C₈ cycloalkyl,and C₁-C₆ alkyl substituted with at least one of morpholinyl,piperidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, phenyl, naphthyl,thiomorpholinyl S,S-dioxide, pyrrolidinyl, pyridyl, pyridazyl,pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, or 4 R₆ groups, wherein R₆ ateach occurrence is independently selected from the group consisting ofhalogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.
 4. Thecompound according to claim 1, wherein R₅ is -M-G-A, wherein M isphenyl, wherein M is unsubstituted or substituted with 1, 2, 3, or 4groups that are independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, haloC₁-C₆ alkoxy, and hydroxy C₁-C₆ alkyl, and A is selected from the groupconsisting of pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl,benzo[1,3]dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,tetrahydronaphthyl, and dihydronaphthyl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, haloC₁-C₆ alkyl, halo C₁-C₆ alkoxy, CN, and NO₂; or M is selected from thegroup consisting of pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, and pyrrolyl, wherein M is unsubstituted or substituted with1, 2, 3, or 4 groups that are independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halo C₁-C₆alkyl, halo C₁-C₆ alkoxy, and hydroxy C₁-C₆ alkyl, and A is selectedfrom the group consisting of phenyl, naphthyl, tetrahydronaphthyl, anddihydronaphthyl, wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently selectedfrom halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆alkoxy, CN, and NO₂; and G is selected from a direct bond between M andA, CH₂, O, S, SO, and SO₂.
 5. The compound according to claim 1, whereinR₁ is hydrogen, C₁-C₆ alkyl or benzyl; R₂ is hydrogen, C₁-C₆ alkyl orbenzyl; and R₃ is -Z-Q-J, wherein Z is C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkyl, or C₁-C₆ alkylthio C₁-C₆ alkyl, each of which is unsubstituted orsubstituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; Q is adirect bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl,piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, orazocanyl wherein each of the above is unsubstituted or substituted with1 or 2 groups that are independently C₁-C₄ alkyl, halogen, or C₁-C₄alkoxy; J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein R₇ is selectedfrom the group consisting of H, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl,phenyl C₁-C₆ alkanoyl and —C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ areindependently H, or C₁-C₆ alkyl, and R₈ and R₉ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl,thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C₁-C₆alkyl, pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, andpyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl,pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, and furyl C₁-C₆ alkyl,wherein each of the above is unsubstituted or substituted with 1, 2, 3,or 4 R₆ groups; or R₈ and R₉ and the nitrogen to which they are attachedform a 5, 6 or 7 membered heterocycloalkyl ring, which is unsubstitutedor substituted with 1, 2, or 3 groups that are independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, and halogen; or R₇, R₈, and thenitrogens to which they are attached form a 5, 6, or 7 memberedheterocycloalkyl group that is unsubstituted or substituted with 1, 2 or3 groups that are independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, and halogen, wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, or 4 R₆ groups, wherein R₆ at each occurrenceis independently selected from the group consisting of halogen, hydroxy,NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃; and R₉ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆alkyl, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl substituted with at least oneof morpholinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl S-oxide,phenyl, naphthyl, thiomorpholinyl S,S-dioxide, pyrrolidinyl, pyridyl,pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of theabove is unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups; R₄is selected from the group consisting of H, C₁-C₄ alkyl, benzyl andphenethyl, wherein the benzyl and phenethyl groups are unsubstituted orsubstituted with 1, 2, 3, or 4 R₆ groups; R₅ is -M-G-A, wherein M isphenyl, wherein M is unsubstituted or substituted with 1, 2, 3, or 4groups that are independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, haloC₁-C₆ alkoxy, and hydroxy C₁-C₆ alkyl; A is selected from the groupconsisting of pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl,benzo[1,3]dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,wherein each of the above is unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkoxy, CN, or NO₂; or M isselected from the group consisting of pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, thiophenyl, and pyrrolyl, wherein M is unsubstituted orsubstituted with 1, 2, 3, or 4 groups that are independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkoxy, and hydroxy C₁-C₆ alkyl,and A is selected from the group consisting of phenyl, naphthyl,tetrahydronaphthyl, and dihydronaphthyl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, haloC₁-C₆ alkoxy, CN, or NO₂; and G is selected from a direct bond between Mand A, CH₂, O, S, SO, and SO₂.
 6. The compound according to claim 5,wherein R₅ is -M-G-A, wherein M is phenyl which is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently selected fromthe group consisting of F, Cl, Br, C₁-C₄ alkyl, hydroxy, methoxy,ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄ alkyl, halo C₁-C₄ alkoxy, andhydroxy C₁-C₄ alkyl, and A is selected from the group consisting ofpyridyl, pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, anddihydronaphthyl, wherein each is unsubstituted or substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofF, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, —CN,and —NO₂; or M is selected from the group consisting of pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl, each ofwhich is unsubstituted or substituted with 1, 2, or 3 groups that areindependently selected from the group consisting of F, Cl, Br, C₁-C₄alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl, and A is selectedfrom the group consisting of phenyl, naphthyl, tetrahydronaphthyl anddihydronaphthyl, wherein each is unsubstituted or substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofF, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, —CN,and —NO₂; and G is selected from a direct bond between M and A, CH₂, O,S, SO, and SO₂.
 7. The compound according to claim 6, wherein R₃ is-Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆alkylthio C₁-C₆ alkyl, each of which is unsubstituted or substitutedwith 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Q is a directbond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl,imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each isunsubstituted or substituted with 1 or 2 groups that are independentlyC₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; J is —C(═NR₇)NR₈R₉ or—NH—C(═NR₇)NR₈R₉, wherein R₇ is selected from the group consisting of H,CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein R₁₀ andR₁₁ are independently H, or C₁-C₆ alkyl, and R₈ and R₉ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein each of theabove is unsubstituted or substituted with 1, 2, 3, or 4 R₆ groups;wherein R₆ at each occurrence is independently selected from the groupconsisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, andOCF₃; or R₈ and R₉ and the nitrogen to which they are attached form a 5or 6 membered heterocycloalkyl ring, which is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, or halogen.
 8. The compound according to claim 6,wherein R₃ is -Z-Q-J wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkyl, or C₁-C₆ alkylthio C₁-C₆ alkyl, each of which is unsubstituted orsubstituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Qis piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, orthiomorpholinyl, wherein each is unsubstituted or substituted with 1 or2 groups that are independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy;and J is —C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein R₇ is selected fromthe group consisting of H, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, and—C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ are independently H, or C₁-C₆ alkyl,and R₈ and R₉ are independently selected from the group consisting of H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy C₁-C₆ alkyl, morpholinylC₁-C₆ alkyl, thiomorpholinyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkylC₁-C₆ alkyl, wherein each of the above is unsubstituted or substitutedwith 1, 2, 3, or 4 R₆ groups; wherein R₆ at each occurrence isindependently selected from the group consisting of halogen, hydroxy,NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃.
 9. The compound as inclaim 1 of structural formula II

wherein R₃, R₄, and R₅ are as defined in claim
 1. 10. The compoundaccording to claim 9, of structural formula III

wherein R₃ is -Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkyl, or C₁-C₆ alkylthio C₁-C₆ alkyl, each of which is unsubstituted orsubstituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Qis a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl,piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, orazocanyl wherein each is unsubstituted or substituted with 1 or 2 groupsthat are independently C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; J is—C(═NR₇)NR₈R₉ or —NH—C(═NR₇)NR₈R₉, wherein R₇ is selected from the groupconsisting of H, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆alkanoyl and —C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ are independently H, orC₁-C₆ alkyl, R₈ and R₉ are independently selected from the groupconsisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy C₁-C₆ alkyl,morpholinyl C₁-C₆ alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide,thiomorpholinyl S-oxide, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆alkyl, imidazolidinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, phenyl C₁-C₆ alkyl, and pyridyl C₁-C₆ alkyl, pyridazylC₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆alkyl, and furyl C₁-C₆ alkyl, wherein each of the above is unsubstitutedor substituted with 1, 2, 3, or 4 R₆ groups; or R₈ and R₉ and thenitrogen to which they are attached form a 5, 6 or 7 memberedheterocycloalkyl ring, which is unsubstituted or substituted with 1, 2,or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy,or halogen; or R₇, R₈, and the nitrogens to which they are attached forma 5, 6, or 7 membered heterocycloalkyl group that is unsubstituted orsubstituted with 1, 2 or 3 groups that are independently C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, or halogen; wherein each of the above isunsubstituted or substituted with 1, 2, 3, or 4 R₆ groups; wherein R₆ ateach occurrence is independently selected from the group consisting ofhalogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃; and R₅is -M-G-A, wherein M is phenyl which is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently selected from the groupconsisting of F, Cl, Br, C₁-C₄ alkyl, hydroxy, methoxy, ethoxy,isopropoxy, CF₃, OCF₃, halo C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and hydroxyC₁-C₄ alkyl, and A is selected from the group consisting of pyridyl,pyrimidyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl, isoquinolinyl, andtetrahydroisoquinolinyl, wherein each is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently selected from the groupconsisting of F, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl,CF₃, OCF₃, CN, and NO₂; or M is selected from pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, thiophenyl and pyrrolyl, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently selected from the group consisting of F, Cl, Br, C₁-C₄alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl; and A is selectedfrom the group consisting of phenyl, naphthyl, tetrahydronaphthyl anddihydronaphthyl, wherein each is unsubstituted or substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofF, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN,and NO₂; and G is selected from a direct bond between M and A, CH₂, O,S, SO, and SO₂.
 11. The compound according to claim 10, wherein R₃ is-Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆alkylthio C₁-C₆ alkyl, each of which is unsubstituted or substitutedwith 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Q is a directbond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl,imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each isunsubstituted or substituted with 1 or 2 groups that are independentlyC₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; J is —C(═NR₇)NR₈R₉ or—NH—C(═NR₇)NR₈R₉, wherein R₇ is selected from the group consisting of H,CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein R₁₀ andR₁₁ are independently H, or C₁-C₆ alkyl, R₈ and R₉ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆alkyl, pyrrolidinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, benzyl, phenethyl, and pyridyl C₁-C₆ alkyl, pyridazyl C₁-C₆alkyl, and furyl C₁-C₆ alkyl, wherein each of the above is unsubstitutedor substituted with 1, 2, 3, or 4 R₆ groups; or R₈ and R₉ and thenitrogen to which they are attached form a 5, 6 or 7 memberedheterocycloalkyl ring, which is unsubstituted or substituted with 1, 2,or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy,or halogen; or R₇, R₈, and the nitrogens to which they are attached forma 5, 6, or 7 membered heterocycloalkyl group that is unsubstituted orsubstituted with 1, 2 or 3 groups that are independently C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, or halogen; wherein R₆ at each occurrence isindependently selected from the group consisting of halogen, hydroxy,NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃; and R₅ is -M-G-A, whereinM is phenyl which is unsubstituted or substituted with 1, 2, or 3 groupsthat are independently selected from the group consisting of F, Cl, Br,C₁-C₄ alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl, and A is selectedfrom the group consisting of pyridyl, and benzo[1,3]dioxyl, anddihydronaphthyl, wherein each is unsubstituted or substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofF, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN,and NO₂; or M is selected from the group consisting of pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl, each ofwhich is unsubstituted or substituted with 1, 2, or 3 groups that areindependently selected from the group consisting of F, Cl, Br, C₁-C₄alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl, and A is selectedfrom the group consisting of phenyl, naphthyl, tetrahydronaphthyl anddihydronaphthyl, wherein each is unsubstituted or substituted with 1, 2,or 3 groups that are independently selected from the group consisting ofF, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN,and NO₂; and G is selected from a direct bond between M and A, CH₂, andO.
 12. The compound according to claim 11, of structural formula IV

wherein R₃ is defined in claim 17; X is CH or CR₁₁; R₁₂ and R₁₃ are ateach occurrence are independently selected from the group consisting ofH, halogen, CF₃, C₁-C₄ alkyl, and C₁-C₄ alkoxy; M is selected from thegroup consisting of phenyl which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consistingof F, Cl, Br, C₁-C₄ alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃,OCF₃, halo C₁-C₄ alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl, andA is selected from the group consisting of pyridyl, andbenzo[1,3]dioxyl, wherein each is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consistingof F, Cl, Br, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃,CN, and NO₂; or M is selected from the group consisting of pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl, each ofwhich is unsubstituted or substituted with 1, 2, or 3 groups that areindependently selected from the group consisting of F, Cl, Br, C₁-C₄alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF₃, OCF₃, halo C₁-C₄alkyl, halo C₁-C₄ alkoxy, and hydroxy C₁-C₄ alkyl, and A is selectedfrom the group consisting of phenyl, naphthyl, and tetrahydronaphthyl,wherein each is unsubstituted or substituted with 1, 2, or 3 groups thatare independently selected from the group consisting of F, Cl, Br, C₁-C₄alkyl, C₁-C₄ alkoxy, halo C₁-C₄ alkyl, CF₃, OCF₃, CN, and NO₂; and G isselected from the group consisting of a direct bond between M and A,CH₂, and O.
 13. The compound according to claim 12, of structuralformula V

wherein R₃, is as defined in claim 18, A is phenyl, 3-fluorophenyl,4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, benzo[1,3]dioxyl,3,5-dimethylphenyl, 2-naphthyl, or 2-tetrahydronaphthyl; G is a directbond between M and A, or G is oxygen; and R₁₂ and R₁₃ are independentlyH, fluoro, chloro, CF₃, methyl or methoxy.
 14. The compound according toclaim 13, wherein R₃ is -Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, or C₁-C₆ alkylthio C₁-C₆ alkyl, each of which isunsubstituted or substituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄alkoxy groups; Q is a direct bond between Z and J or —C(═O)—, J is—NH—C(═NR₇)NR₈R₉, wherein R₇ is selected from the group consisting of H,CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkanoyl, and —C(═O)NR₁₀R₁₁, wherein R₁₀ andR₁₁ are independently H, or C₁-C₆ alkyl, and R₈ and R₉ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, alkoxy C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl,and C₃-C₈ cycloalkyl C₁-C₆ alkyl, wherein each of the above isunsubstituted or substituted with 1, 2, 3, or 4 R groups, wherein R₆ ateach occurrence is independently selected from the group consisting ofhalogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃, or R₈and R₉ and the nitrogen to which they are attached form a 5, 6 or 7membered heterocycloalkyl ring, which is unsubstituted or substitutedwith 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, or halogen.
 15. The compound according to claim 13, wherein R₃is -Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, orC₁-C₆ alkylthio C₁-C₆ alkyl, each of which is unsubstituted orsubstituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Qis a direct bond between Z and J or —C(O)—, J is —NH—C(═NR₇)NR₈R₉,wherein R₇, R₈, and the nitrogens to which they are attached form a 5,6, or 7 membered heterocycloalkyl group that is unsubstituted orsubstituted with 1, 2 or 3 groups that are independently C₁-C₆ alkyl,C₁-C₆ alkoxy, hydroxy, or halogen; and R₉ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl,C₃-C₈ cycloalkyl, and C₁-C₆ alkyl substituted with at least one ofmorpholinyl, piperidinyl, thiomorpholinyl, phenyl, naphthyl,pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl,wherein each of the above is unsubstituted or substituted with 1, 2, 3,or 4 R₆ groups, wherein R₆ at each occurrence is independently selectedfrom the group consisting of halogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆alkoxy, CF₃, and OCF₃.
 16. The compound according to claim 13, whereinR₃ is -Z-Q-J, wherein Z is a C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, orC₁-C₆ alkylthio C₁-C₆ alkyl, each of which is unsubstituted orsubstituted with 1 or 2 C₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy groups; Qis a direct bond between Z and J, piperidinyl, pyrrolyl, piperazinyl,imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each isunsubstituted or substituted with 1 or 2 groups that are independentlyC₁-C₄ alkyl, halogen, or C₁-C₄ alkoxy; J is —C(═NR₇)NR₈R₉ wherein R₇ isselected from the group consisting of H, CN, NO₂, C₁-C₆ alkyl, C₁-C₆alkanoyl, and —C(═O)NR₁₀R₁₁, wherein R₁₀ and R₁₁ are independently H, orC₁-C₆ alkyl, R₈ and R₉ are independently selected from the groupconsisting of H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, alkoxy C₁-C₆ alkyl,morpholinyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl C₁-C₆alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R₆ groups; or R₈ and R₉ and the nitrogen to which they areattached form a 5, 6 or 7 membered heterocycloalkyl ring, which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, or halogen; wherein R₆at each occurrence is independently selected from the group consistingof halogen, hydroxy, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, and OCF₃. 17.A compound or pharmaceutically acceptable salt thereof of structuralformula VIII:

wherein R₃ is selected from:

and R₅ is selected from:


18. A compound or pharmaceutically acceptable salt thereof listed in thefollowing table: 13N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide, 29N¹-hydroxy-5-morpholin-4-yl-N²-[(4-phenoxyphenyl)sulfonyl]-D-norvalinamide,30N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-5-morpholin-4-yl-D-norvalinamide, 32N¹-hydroxy-6-morpholin-4-yl-N²-[(4-phenoxyphenyl)sulfonyl]-D-norleucinamide,33N²-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide, 34N²-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide, 35N²-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide, 36N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide, 44N²-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide, 45N²-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide, 46N²-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide, 47N²-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide, 49N⁶-[(Z)-(cyanoimino)(cyclopropylamino)methyl]-N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N¹-hydroxy-D-lysinamide, 50N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-3-ylalaninamide,51N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyrrolidin-3-ylalaninamide,53 N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-tryptophanamide, 56N¹-hydroxy-N²-methyl-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-3-ylalaninamide, 57N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-4-ylalaninamide,58N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyridin-3-yl-D-alaninamide,59 N⁶-glycyl-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide,60 N¹-hydroxy-N²,N⁶,N⁶-trimethyl-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide, 61 3-[4-(aminomethyl)cyclohexyl]-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}alaninamide, 65N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-lysinamide, 69N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-N⁶-(morpholin-4-ylcarbonyl)-D-lysinamide, 704-cyano-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-phenylalaninamide,714-cyano-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-phenylalaninamide, 723-cyano-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-phenylalaninamide, 733-cyano-N¹-hydroxy-N²-{[4-(phenyloxy)phenyl]sulfonyl}-D-phenylalaninamide,76N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-N⁶-({[2-(methyloxy)ethyl]amino}carbonyl)-D-lysinamide, 77N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N⁶-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]-N¹-hydroxy-D-lysinamide, 79N²-{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N¹-hydroxy-6-morpholin-4-yl-D-norleucinamide, 80N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-3-morpholin-4-yl-D-alaninamide, 83N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]alaninamide, 87N⁵-(aminocarbonyl)-N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxy-D-ornithinamide, 88(2R)—N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-4-(dimethylamino)-N¹-hydroxybutanamide, 89(2R)—N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-4-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-2-methylbutyl]amino}-N¹-hydroxybutanamide, 90N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide, 91(2R)-4-amino-N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxybutanamide, 93N²-[({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide, 94N²-[({4-[(4-chlorophenyl)oxy]-3-fluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide, 95N²-[({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide, 96N²-[({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide, 97N²-({[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}amino)-N¹-hydroxy-2-piperidin-4-ylacetamide, 98N²-[({4-[(3,5-dimethylphenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N¹-hydroxy-2-piperidin-4-ylacetamide, 993-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxyalaninamide, 1003-[4-(aminomethyl)cyclohexyl]-N²-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide, 1013-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-chlorophenyl)oxy]-3-fluorophenyl}sulfonyl)-N¹-hydroxyalaninamide, 1023-[4-(aminomethyl)cyclohexyl]-N²-({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide, 1033-[4-(aminomethyl)cyclohexyl]-N²-({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N¹-hydroxyalaninamide, 104N²-({[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}amino)-N¹-hydroxy-2-piperidin-4-ylacetamide, and 1053-[4-(aminomethyl)cyclohexyl]-N²-({4-[(3,5-dimethylphenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N¹-hydroxyalaninamide.


19. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 20. A method oftreating breast cancer, arthritis, and stroke comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a pharmaceutical composition according to claim 19.